Synthetic methods for preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-n-[(1s)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-n-prop-2-ynyl-1,3-thiazol-2-amine

ABSTRACT

The present disclosure relates to the fields of chemistry and medicine, more particularly to processes for making 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), pharmaceutically acceptable salts, and crystalline forms thereof, for the treatment of congenital adrenal hyperplasia (CAH).

FIELD OF THE INVENTION

The present disclosure relates to the fields of chemistry and medicine, more particularly to processes for making 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), pharmaceutically acceptable salts, and crystalline forms thereof, for the treatment of congenital adrenal hyperplasia (CAH).

BACKGROUND OF THE INVENTION

Classic congenital adrenal hyperplasia (CAH) is a disease that includes a group of autosomal recessive disorders that result in an enzyme deficiency that alters the production of adrenal steroids due to 21-hydroxylase deficiency, a condition that results in little or no cortisol biosynthesis. One clinical manifestation of the absence of cortisol is the lack of feedback inhibition of pituitary adrenocorticotropic hormone (ACTH) secretion. Increased ACTH levels cause adrenal hyperplasia and the enzyme mutation causes a shunting of cortisol precursor steroids to alternate pathways. Most notably, the shunting of androgens leads to virilization and other developmental complications in females and the over-accumulation of ACTH is associated with the formation of testicular adrenal rest tumors in males. In addition, since the same enzyme (21-hydroxylase) is used in the pathway for the biosynthesis of the mineralocorticoids, a number of these patients suffer from aldosterone deficiency which can result in dehydration and death due to salt-wasting. The prevalence of classic 21-hydroxylase deficiency CAH in the US general population, based on newborn screening, has been documented as 1:10,000 to 1:20,800 (Trakakis et al., “An update to 21-hydroxylase deficient congenital adrenal hyperplasia,” Gynecol. Endocrinol. (2010) 26(1):63-71; Hertzberg et al., “Birth prevalence rates of newborn screening disorders in relation to screening practices in the United States,” J. Pediatr. (2011) 159(4):555-560).

Pediatric patients from birth through adolescence, and females in particular, appear to be the most vulnerable population of CAH sufferers and represent the subgroup of patients with the greatest unmet medical need (Cheng and Speiser, “Treatment outcomes in congenital adrenal hyperplasia,” Adv. Pediatr. (2012) 59(1):269-281; Merke and Poppas, “Management of adolescents with congenital adrenal hyperplasia,” Lancet Diabetes Endocrinol. (2013) 1(4):341-352). Excessive androgen production in these younger patients results in early onset puberty and adrenarche, changes in skeletal maturation patterns, short stature caused by premature growth plate fusion, as well as significant hirsutism and acne problems. While survival is properly ensured through steroid replacement strategies based on physiologic dosing of glucocorticoids (e.g., hydrocortisone) and mineralocorticoids (e.g., fludrocortisone), these doses are often inadequate to suppress the accumulating ACTH and overproduction of progestogens and androgens (e.g., 17-hydroxyprogesterone [17-OHP], androstenedione, and testosterone). The uncontrolled symptoms of androgen excess, indeed, have a substantial impact on the day-to-day functioning and development of these patients.

Currently, exogenous corticosteroids are the standard of care for treating patients with classic CAH. This treatment is used to correct the cortisol deficiency and reduce the excessive ACTH levels and androgen excess. However, the dose and duration of steroid use required to suppress ACTH are typically well above the normal physiological level used for cortisol replacement alone (as in patients with Addison’s disease). This increased exposure to glucocorticoids can lead to iatrogenic Cushing’s syndrome, increased cardiovascular risk factors, glucose intolerance, reduced growth velocity, and decreased bone mineral density in CAH patients (Elnecave et al., “Bone mineral density in girls with classical congenital adrenal hyperplasia due to CYP21 deficiency,” J. Pediatr. Endocrinol. Metab. (2008) 21(12):1155-1162; King et al., “Long-term corticosteroid replacement and bone mineral density in adult women with classical congenital adrenal hyperplasia,” J. Clin. Endocrinol. Metab. (2006) 91(3):865-869; and Migeon and Wisniewski, “Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Growth, development, and therapeutic considerations,” Endocrinol. Metab. Clin. North Am. (2001) 30(1):193-206).

It has been demonstrated in clinical trials that orally active compounds that block CRF₁, such as 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), provide a reduction from baseline in 17-hydroxyprogesterone (17-OHP) and androstenedione levels in amounts believed to allow use of lower, more physiologic doses of glucocorticoid (e.g. hydrocortisone) in patients with CAH. The structure of Compound 1 is shown below:

Accordingly, a significant need exists for efficient methods for the preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) to support further clinical trials and commercial efforts.

SUMMARY OF THE INVENTION

The present invention provides, inter alia, processes for the preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) and intermediates related thereto.

The processes and intermediates of the present invention are useful in preparing 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), pharmaceutical salts, crystalline forms, and pharmaceutical compositions that are useful in the treatment of corticotropin releasing factor 1 (CRF₁) receptor-mediated disorders.

One aspect of the present invention pertains to processes for preparing 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof:

comprising: alkylating (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof:

with a Compound of Formula (Ii):

wherein: LG is a leaving group;

-   in the presence of an alkylating-step solvent, a phase-transfer     catalyst, an alkylating-step base, and water to form     4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine     (Compound 1) or a pharmaceutically acceptable salt thereof.

One aspect of the present invention pertains to processes for preparing (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof:

comprising:

-   cyclizing (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine     (Compound 6A) or a salt thereof:

-   

-   with 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one     (Compound 8A) or a tautomeric form thereof:

-   

-   in the presence of a cyclizing-step solvent to form     (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine     (Compound 9A) or a salt thereof.

One aspect of the present invention pertains to processes for preparing (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof:

comprising:

-   deprotecting a Compound of Formula (Ig), or a salt thereof,

-   

-   wherein:

-   R^(1c), R^(2c), and R^(3c) are each independently selected from: H,     C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen;

-   in the presence of a deprotecting-catalyst, hydrogen, and a     deprotecting-step solvent to form     (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound     6A) or a salt thereof.

One aspect of the present invention pertains to processes for preparing a Compound of Formula (Ig), or a salt thereof,

wherein:

-   R^(1c), R^(2c), and R^(3c) are each independently selected from: H,     C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen;

-   comprising: reducing a Compound of Formula (Ie):

-   

-   in the presence of a reducing-catalyst, hydrogen, and a     reducing-step solvent to form a Compound of Formula (Ig), or a salt     thereof.

One aspect of the present invention pertains to processes for preparing a Compound of Formula (Ie):

wherein:

-   R^(1c), R^(2c), and R^(3c) are each independently selected from: H,     C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen; -   comprising:     -   condensing 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one         (Compound 3A):

    -   

    -   with a Compound of Formula (Ic), or a salt thereof:

    -    -   in the presence of a condensing-step acid and a condensing-step     solvent to a Compound of Formula (Ie).

One aspect of the present invention pertains to processes for preparing 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A):

comprising:

-   reacting 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A):

-   

-   -   with an organomagnesium reagent of         4-bromo-2-fluoro-1-methylbenzene in the presence of a reacting         -step solvent to form         2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound         3A).

One aspect of the present invention pertains an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base).

One aspect of the present invention pertains to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt).

One aspect of the present invention pertains to pharmaceutical compositions comprising a crystalline form (Compound 1, free base) as described herein, and a pharmaceutically acceptable carrier.

One aspect of the present invention pertains to pharmaceutical products selected from: a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a crystalline form (Compound 1, free base) as described herein.

One aspect of the present invention pertains to pharmaceutical compositions comprising a crystalline form (Compound 1, tosylate salt) as described herein, and a pharmaceutically acceptable carrier.

One aspect of the present invention pertains to pharmaceutical products selected from: a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a crystalline form (Compound 1, tosylate salt) as described herein.

One aspect of the present invention pertains to compositions comprising:

-   a.     4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine     (Compound 1), or a pharmaceutically acceptable salt thereof; and -   b. at least one compound selected from:     -   (S)-4-(2-Chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine         (Compound 9A);     -   (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(p-tolyl)ethyl)-5-methyl-N         (prop-2-yn-1-yl)thiazol-2-amine (Compound IIa);     -   (S)-4-(2-chloro-5-methyl-4-(prop-2-yn-1-yloxy)phenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine         (Compound IIb);     -   4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1R)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-(2-propyn-1-yl)-2-thiazolamine         (Compound IIc);     -   ethanol; and     -   propargyl bromide.

One aspect of the present invention pertains to methods of treating a disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form (Compound 1, free base) as described herein; a crystalline form (Compound 1, tosylate base) as described herein; a pharmaceutical composition as described herein; a pharmaceutical product as described herein; or a composition as described herein; wherein the subject has abnormal levels of CRF₁.

One aspect of the present invention pertains to methods of treating a Corticotropin Releasing Factor 1 (CRF₁) disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form (Compound 1, free base) as described herein; a crystalline form (Compound 1, tosylate base) as described herein; a pharmaceutical composition as described herein; a pharmaceutical product as described herein; or a composition as described herein.

One aspect of the present invention pertains to methods of treating congenital adrenal hyperplasia (CAH), in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form (Compound 1, free base) as described herein; a crystalline form (Compound 1, tosylate base) as described herein; a pharmaceutical composition as described herein; a pharmaceutical product as described herein; or a composition as described herein.

One aspect of the present invention pertains to uses of an anhydrous crystalline form (Compound 1, free base) as described herein; or the crystalline form (Compound 1, tosylate base) as described herein; for the manufacture of a medicament for the treatment of a subject wherein the subject has abnormal levels of CRF₁.

One aspect of the present invention pertains to uses of an anhydrous crystalline form (Compound 1, free base) as described herein; or the crystalline form (Compound 1, tosylate base) as described herein; for the manufacture of a medicament for the treatment of a Corticotropin Releasing Factor 1 (CRF₁) disorder.

One aspect of the present invention pertains to uses of an anhydrous crystalline form (Compound 1, free base) as described herein; or the crystalline form (Compound 1, tosylate base) as described herein; for the manufacture of a medicament for the treatment of congenital adrenal hyperplasia (CAH).

One aspect of the present invention pertains to an anhydrous crystalline form (Compound 1, free base) as described herein; a crystalline form (Compound 1, tosylate base) as described herein; a pharmaceutical composition as described herein; a pharmaceutical product as described herein; or a composition as described herein; for use in a method of treatment of the human or animal body by therapy.

One aspect of the present invention pertains to an anhydrous crystalline form (Compound 1, free base) as described herein; a crystalline form (Compound 1, tosylate base) as described herein; a pharmaceutical composition as described herein; a pharmaceutical product as described herein; or a composition as described herein; for use in a method of treatment of a disorder in a subject wherein the subject has abnormal levels of CRF₁.

One aspect of the present invention pertains to an anhydrous crystalline form (Compound 1, free base) as described herein; a crystalline form (Compound 1, tosylate base) as described herein; a pharmaceutical composition as described herein; a pharmaceutical product as described herein; or a composition as described herein; for use in a method of treatment of a Corticotropin Releasing Factor 1 (CRF₁) disorder.

One aspect of the present invention pertains to an anhydrous crystalline form (Compound 1, free base) as described herein; a crystalline form (Compound 1, tosylate base) as described herein; a pharmaceutical composition as described herein; a pharmaceutical product as described herein; or a composition as described herein; for use in a method of treating congenital adrenal hyperplasia (CAH).

One aspect of the present invention pertains to Compounds of Formula (Ie):

wherein:

-   R^(1c), R^(2c), and R^(3c) are each independently selected from: H,     C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen.

One aspect of the present invention pertains to Compounds of Formula (Ig) or a salt thereof:

wherein:

-   R^(1c), R^(2c), and R^(3c) are each independently selected from: H,     C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen.

One aspect of the present invention pertains to processes for preparing a pharmaceutical composition comprising admixing a crystalline form (Compound 1, free base) as described herein; a crystalline form (Compound 1, tosylate base) as described herein; or a composition according as described herein; and a pharmaceutically acceptable carrier.

These and other aspects of the invention disclosed herein will be set forth in greater detail as the patent disclosure proceeds.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows an exemplary X-ray powder diffraction (XRPD) pattern for a sample of crystalline Form I of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) prepared according to Example 3.

FIG. 2 shows an exemplary Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) thermograms for a sample of crystalline Form I of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) prepared according to Example 3.

FIG. 3 shows an exemplary Gravimetric Vapor Sorption (GVS) for a sample of crystalline Form I of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) as described in Example 4.

FIG. 4 shows general synthetic schemes for the preparation of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A), 4-Chloro-2-(methoxy-¹³C-d₃)-1-methylbenzene (Compound 7A′), and 1-(2-Chloro-4-(methoxy-¹³C-d₃)-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A′). The synthesis of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A) has previously been described in International Publication No. WO2010/125414 by Sanofi-Aventis.

FIG. 5 shows a general scheme for the preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1).

FIG. 6 shows a general scheme for the preparation of (S)-4-(2-chloro-4-(methoxy-¹³C-_(d3))-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound 3).

FIG. 7 shows an exemplary X-ray powder diffraction (XRPD) pattern for a sample of crystalline Form I of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1).

FIG. 8 shows an overlay of the exemplary X-ray powder diffraction (XRPD) patterns from FIG. 1 and FIG. 7 for crystalline Form I of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), and although the intensities for certain peaks are rather dramatic, the overlay clearly shows substantially the same peak positioning.

FIG. 9 shows an exemplary X-ray powder diffraction (XRPD) pattern for a sample of crystalline (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A).

FIG. 10 shows an exemplary Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) thermograms for a sample of crystalline (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A).

FIG. 11 shows an exemplary X-ray powder diffraction (XRPD) pattern for a sample of crystalline 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A).

FIG. 12 shows an exemplary Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) thermograms for a sample of crystalline 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A).

FIG. 13 shows an exemplary X-ray powder diffraction (XRPD) pattern for a sample of crystalline (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt).

FIG. 14 shows an exemplary Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) thermograms for a sample of crystalline (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt).

FIG. 15 shows an exemplary X-ray powder diffraction (XRPD) pattern for a sample of crystalline 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A).

FIG. 16 shows an exemplary Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) thermograms for a sample of crystalline 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A).

FIG. 17 shows an exemplary X-ray powder diffraction (XRPD) pattern for a sample of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt).

FIG. 18 shows an exemplary Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) thermograms for a sample of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt).

FIG. 19 shows the dissolution performance of several spray-dried dispersion formulations in 0.5 wt% simulated intestinal fluid (SIF) in phosphate buffered saline (PBS), pH 6.5.

FIG. 20 shows the vertical membrane flux cell integrated in the µDiss Profiler™ used for the membrane flux assay.

FIG. 21 shows non-sink dissolution data for several spray-dried dispersion formulations and the compound of Formula (I) in 0.5 wt% SIF in PBS, pH 6.5.

FIG. 22 is a graph showing membrane flux of 1 mg/mL GB/IB 0.5 wt% SIF doses of Compound 1 and various spray-dried dispersion formulations over time. The solid lines indicate flux (µg min-1 cm-2) and the broken lines indicate concentration (µg/mL) in 0.5% SIF.

FIG. 23 is a flow diagram of the spray drying manufacturing process used to prepare a 1000 g batch of an SDD containing 25% of Compound 1 and 75% PVP/VA 64.

FIG. 24 shows an exemplary X-ray powder diffraction (XRPD) pattern for a sample of crystalline Form I of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt).

FIG. 25 shows an exemplary Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) thermograms for a sample of crystalline Form I of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt).

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

The term “about” preceding a temperature have an allowable variability of ±5° C. In all other instances, unless otherwise specified, the term “about” preceding a stated value includes the stated value and also includes ±20% of the stated value, and includes more specifically values of ±10%, ±5%, ±2%, and ±1% of the stated value.

To provide a more concise description, some of the quantitative expressions herein are recited as a range from about amount X to about amount Y. It is understood that when a range is recited, the range is not limited to the recited upper and lower bounds, but rather includes the full range from about amount X through about amount Y, or any range therein.

As used herein, “room temperature”, or “RT”, refers to the ambient temperature of a typical laboratory, which is generally around 25° C.

As used herein, “administration”, or “administering”, refers to a method of giving a dosage of a compound or pharmaceutical formulation to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian. The preferred method of administration can vary depending on various factors, e.g., the components of the pharmaceutical formulation, the site of the disease, and the severity of the disease.

The term “C₆-C₁₀ aryl” refers to a saturated ring system containing 6 to 10 carbon atoms that can contain a single ring or two fused rings and is aromatic, such as phenyl and naphthalenyl. When one or more substituents are present on the “aryl” ring, the substituent(s) can be bonded at any available ring carbon.

The term “C₁-C₆ alkyl” and “C₁-C₄ alkyl” refers to a saturated straight or branched carbon radical containing 1 to 6 carbons (i.e., “C₁-C₆ alkyl”) or 1 to 4 carbons (i.e., “C₁-C₄ alkyl”). Some embodiments are 1 to 5 carbons (i.e., C₁-C₅ alkyl), some embodiments are 1 to 3 carbons (i.e., C₁-C₃ alkyl), and some embodiments are 1 or 2 carbons. Examples of an alkyl group include: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neo-pentyl, 1-methylbutyl [i.e., —CH(CH₃)CH₂CH₂CH₃], 2-methylbutyl [i.e., —CH₂CH(CH₃)CH₂CH₃], n-hexyl and the like.

The term “C₁-C₄ alkylsulphonyloxy” refers to a radical consisting of a C₁-C₄ alkyl group attached directly to the sulfur of an SO₃ group. The “C₁-C₄ alkylsulphonyloxy” group can be represented by the formula: C₁-C₄ alkylS(═O)₂O— or the following:

The term C₁-C₄ alkyl has the same definition as found herein. Examples include: methanesulfonate [CH₃S(═O)₂O—, or (methylsulfonyl)oxy], ethanesulfonate, propanesulfonate, isopropylsulfonate, butanesulfonate, and the like.

The term “C₁-C₆ alkoxy” refers to a radical consisting of a C₁-C₆ alkyl group attached directly to an oxygen atom, wherein C₁-C₆ alkyl has the same definition as found herein. Some embodiments contain 1 to 5 carbons (i.e., C₁-C₅ alkoxy). Some embodiments contain 1 to 4 carbons (i.e., C₁-C₄ alkoxy). Some embodiments contain 1 to 3 carbons (i.e., C₁-C₃ alkoxy). Some embodiments contain 1 or 2 carbons. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, isobutoxy, sec-butoxy, and the like.

The term “amorphous” means a solid that is in a non-crystalline state. Amorphous solids are disordered arrangements of molecules and therefore possess no distinguishable crystal lattice or unit cell and consequently have no definable long-range ordering. The solid-state form of a solid can be determined by polarized light microscopy, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), or other standard techniques known to those of skill in the art.

The term “C₆-C₁₀ arylsulfonyloxy” refers to a radical consisting of an aryl group attached directly to the sulfur atom of an SO₃ group and can be represented by the formula aryl—S(═O)₂O— or the following:

The term aryl has the same definition as found herein. Examples include: benzenesulfonate [PhS(═O)₂O—, or (phenylsulfonyl)oxy, besylate], (naphthalen-1-ylsulfonyl)oxy, and (naphthalen-2-ylsulfonyl)oxy.

The term “composition” refers to a compound or crystalline form thereof, including but not limited to, salts, solvates, and hydrates of a compound of the present invention, in combination with at least one additional component, such as, a composition obtained/prepared during synthesis, preformulation, in-process testing/control (e.g., TLC, HPLC, NMR samples), and the like.

The term “% crystallinity” or “crystalline purity” refers to the percentage of a crystalline form in a preparation or sample. It is understood that the preparation or sample may contain other forms, such as, an amorphous form of the same compound, or different crystalline form(s) of the same compound, or mixtures thereof. In some embodiments, the crystalline form can be isolated as the desired form (i.e., the crystalline form as described herein) with a crystalline purity of at least about 75% by weight, about 80% by weight, about 85% by weight, about 90% by weight, about 95% by weight, about 96% by weight, about 97% by weight, about 98% by weight, or about 99% by weight. In some embodiments, the crystalline form can be isolated with a purity of about 90% or greater by weight. In some embodiments, the crystalline form can be isolated with a purity of about 95% or greater by weight. In some embodiments, the crystalline form can be isolated with a purity of about 99% or greater by weight.

When describing particle size for a sample, “D10”, “D50”, “D90” are used and have the following definitions: the term “D10” as used herein means that 10% of the particles (based on volume) are smaller than or equal to the indicated size; the term “D50” as used herein means that 50% of the particles (based on volume) are smaller than or equal to the indicated size; and the term “D90” as used herein means that 90% of the particles (based on volume) are smaller than or equal to the indicated size. As an example, when a sample as a D10 of 21 µM, then 10% of the particles in that sample are smaller than or equal to 21 µM based on volume.

The term “in need of treatment” and the term “in need thereof” when referring to treatment are used interchangeably to mean a judgment made by a caregiver (e.g. physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals) that an individual or animal requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver’s expertise, but that includes the knowledge that the individual or animal is ill, or will become ill, as the result of a disease, condition or disorder that is treatable by the compounds of the invention. Accordingly, the compounds of the invention can be used in a protective or preventive manner; or compounds of the invention can be used to alleviate, inhibit, or ameliorate the disease, condition, or disorder.

The term “halo” or “halogen” refers to fluoro, chloro, bromo, or iodo. In some embodiments, halogen is chloro, bromo, or iodo. In some embodiments, halogen is fluoro, chloro, or bromo. In some embodiments, halogen is fluoro. In some embodiments, halogen is chloro. In some embodiments, halogen is bromo. In some embodiments, halogen is iodo.

The term “C₁-C₆ haloalkyl” refers to a radical consisting of a C₁-C₆ alkyl group substituted with one or more halogens, wherein C₁-C₆ alkyl has the same definition as found herein. The C₁-C₆ haloalkyl may be fully substituted in which case it can be represented by the formula C_(n)L_(2n+1), wherein L is a halogen and “n” is 1, 2, 3, 4, 5, or 6. When more than one halogen is present then they may be the same or different and selected from: fluorine, chlorine, bromine, and iodine. In some embodiments, haloalkyl contains 1 to 5 carbons (i.e., C₁-C₅ haloalkyl). In some embodiments, haloalkyl contains 1 to 4 carbons (i.e., C₁-C₄ haloalkyl). In some embodiments, haloalkyl contains 1 to 3 carbons (i.e., C₁-C₃ haloalkyl). In some embodiments, haloalkyl contains 1 or 2 carbons. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 4,4,4-trifluorobutyl, and the like.

The term “hydroxyl” refers to the group —OH.

The term “individual” or “subject” refers to any animal, including mammals, such as, mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiment “individual” refers to humans. In the context of a clinical trial or screening or activity experiment the subject may be a healthy volunteer or healthy participant without an underlying CFR -mediated disorder or condition or a volunteer or participant that has received a diagnosis for a disorder or condition in need of medical treatment as determined by a health care professional. In the context outside of a clinical trial a subject under the care of a health care professional who has received a diagnosis for a disorder or condition is typically described as a patient.

The term “inorganic base” refers to a base that does not include at least one C—H bond and includes at least one alkali metal or alkaline earth metal. Examples of an inorganic base include, but are not limited to, barium carbonate, calcium carbonate, cesium carbonate, lithium carbonate, magnesium carbonate, potassium carbonate, sodium carbonate, cesium hydrogen carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, barium hydroxide, calcium hydroxide, cesium hydroxide, lithium hydroxide, magnesium hydroxide, potassium hydroxide, sodium hydroxide, and the like.

As used herein, “leaving group” refers to an atom or a group of atoms that is displaced in a chemical reaction as a stable species. Suitable leaving groups are well known in the art, e.g., see, March’s Advanced Organic Chemistry, 5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001 and T. W. Greene, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, 1999. Such leaving groups include, but are not limited to, halogen, optionally substituted alkylsulphonyloxy, and optionally substituted arylsulfonyloxy. Examples of some leaving groups include chloro, bromo, iodo, mesylate, tosylate, triflate, nosylate, and brosylate.

The term “nitro” refers to the group —NO₂.

The term “pediatric subject” refers to a subject under the age of 21 years at the time of diagnosis or treatment. The term “pediatric” can be further divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)) see e.g., Berhman et al., Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph et al., Rudolph’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery et al., Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.

In some embodiments, a “pediatric subject” is from birth through the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or 12 years of age through 21 years of age (up to, but not including, the twenty-second birthday). In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than seven years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age.

The phrase “pharmaceutically acceptable” refers to compounds (and salts thereof), compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, co-solvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, which are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic formulations is contemplated. Supplementary active ingredients can also be incorporated into the formulations. In addition, various excipients, such as are commonly used in the art, can be included. These and other such compounds are described in the literature, e.g., in the Merck Index, Merck & Company, Rahway, NJ. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (2010); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 12th Ed., The McGraw-Hill Companies.

The term “pharmaceutical composition” refers to a specific composition comprising at least one active ingredient; including but not limited to, salts, solvates, and hydrates of compounds of the present invention, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.

The term “phase-transfer catalyst” is any ionic catalyst, such as quaternary ammonium salts, that can enable the migration of a reactant from one phase into another phase where the reaction occurs. Suitable leaving groups are well known in the art. Examples include, acetylcholine chloride, (2-aminoethyl)trimethylammonium chloride hydrochloride, benzalkonium chloride, benzyldimethyldecylammonium chloride, benzyldimethyldodecylammonium chloride, benzyldimethylhexadecylammonium chloride, benzyldimethylhexylammonium chloride, benzyldimethyloctylammonium chloride, benzyldimethyltetradecylammonium chloride, benzyldodecyldimethylammonium bromide, benzyltributylammonium bromide, benzyltributylammonium chloride, benzyltributylammonium iodide, benzyltriethylammonium bromide, benzyltriethylammonium chloride, benzyltrimethylammonium bromide, benzyltrimethylammonium chloride, (3-carboxypropyl)trimethylammonium chloride, cetyltrimethylammonium chloride, cetyltrimethylammonium hydrogensulfate, choline chloride, decyltrimethylammonium bromide, diallyldimethylammonium chloride, didecyldimethylammonium bromide, didodecyldimethylammonium bromide, dihexadecyldimethylammonium bromide, dimethyldioctadecylammonium bromide, dimethylditetradecylammonium bromide, dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride, dodecylethyldimethylammonium bromide, dodecyltrimethylammonium chloride, domiphen bromide, heptadecafluorooctanesulfonic acid tetraethylammonium salt, hexadecyltrimethylammonium bromide, hexadecyltrimethylammonium chloride, hexyltrimethylammonium bromide, malondialdehyde tetrabutylammonium salt, methyltrioctylammonium bromide, methyltrioctylammonium chloride, methyltrioctylammonium hydrogen sulfate, methyltrioctylammonium thiosalicylate, myristyltrimethylammonium bromide, tetrabutylammonium acetate, tetrabutylammonium benzoate, tetrabutylammonium bisulfate, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium cyanide, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogensulfate, tetrabutylammonium iodide, tetrabutylammonium methanesulfonate, tetrabutylammonium methoxide, tetrabutylammonium nonafluorobutanesulfonate, tetrabutylammonium perchlorate, tetrabutylammonium phosphate monobasic, tetrabutylammonium succinimide, tetrabutylammonium sulfate, tetrabutylammonium tetrabutylborate, tetrabutylammonium tetrafluoroborate, tetrabutylammonium tetraphenylborate, tetrabutylammonium thiocyanate, tetrabutylammonium p-toluenesulfonate, tetrabutylammonium trifluoromethanesulfonate, tetradodecylammonium bromide, tetradodecylammonium chloride, tetraethylammonium acetate tetrahydrate, tetraethylammonium benzoate, tetraethylammonium bicarbonate, tetraethylammonium bromide, tetraethylammonium chloride, tetraethylammonium cyanide, tetraethylammonium hexafluorophosphate, tetraethylammonium iodide, tetraethylammonium tetrafluoroborate, tetraethylammonium p-toluenesulfonate, tetraethylammonium trifluoromethanesulfonate, tetraheptylammonium bromide, tetrahexadecylammonium bromide, tetrahexylammonium bromide, tetrahexylammonium chloride, tetrahexylammonium hexafluorophosphate, tetrahexylammonium hydrogensulfate, tetrahexylammonium iodide, tetrahexylammonium tetrafluoroborate, tetrakis(decyl)ammonium bromide, tetramethylammonium acetate, tetramethylammonium bis(trifluoromethanesulfonyl)imide, tetramethylammoniumbisulfate, tetramethylammonium bromide, tetramethylammonium chloride, tetramethylammonium chloride, tetramethylammonium hexafluorophosphate, tetramethylammonium hydrogen sulfate, tetramethylammonium hydrogensulfate, tetramethylammonium iodide, tetramethylammonium silicate, tetramethylammonium sulfate, tetramethylammonium tetrafluoroborate, tetraoctadecylammonium bromide, tetraoctylammonium bromide, tetraoctylammonium chloride, tetrapentylammonium bromide, tetrapentylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium chloride, tetrapropylammonium iodide, tetrapropylammonium tetrafluoroborate, tributylammonium pyrophosphate, tributylmethylammonium bromide, tributylmethylammonium chloride, tridodecylmethylammonium chloride, tridodecylmethylammonium iodide, triethylhexylammonium bromide, triethylmethylammonium chloride, trihexyltetradecylammonium bromide, trimethyloctadecylammonium bromide, trimethyloctylammonium bromide, trimethyloctylammonium chloride, trimethylphenylammonium bromide, trimethylphenylammonium chloride, trimethyl-tetradecylammonium chloride, and the like.

The term “prescribing” refers to order, authorize, or recommend the use of a drug or other therapy, remedy, or treatment. In some embodiments, a health care provider orally advises, recommends, or authorizes the use of a compound, dosage regimen, or other treatment to an individual. The health care provider may or may not provide a written prescription for the compound, dosage regimen, or treatment. Further, the health care provider may or may not provide the compound or treatment to the individual. For example, the health care provider can advise the individual where to obtain the compound without providing the compound. In some embodiments, a health care provider can provide a written prescription for the compound, dosage regimen, or treatment to the individual. A prescription can be written on paper or recorded on electronic media. In addition, a prescription can be called in (oral) or faxed in (written) to a pharmacy or a dispensary. In some embodiments, a sample of the compound or treatment is given to the individual. As used herein, giving a sample of a compound constitutes an implicit prescription for the compound. Different health care systems around the world use different methods for prescribing and administering compounds or treatments, and these methods are encompassed by the disclosure herein. A health care provider can include, for example, a physician, nurse, nurse practitioner, or other health care professional who can prescribe or administer compounds (drugs) for the disorders disclosed herein. In addition, a health care provider can include anyone who can recommend, prescribe, administer, or prevent an individual from receiving a compound or drug, including, for example, an insurance provider.

The terms “prevent”, “preventing”, and “prevention” refer to the elimination or reduction of the occurrence or onset of one or more symptoms associated with a specific disorder. For example, the terms “prevent”, “preventing”, and “prevention” can refer to the administration of therapy on a prophylactic or preventative basis to an individual who may ultimately manifest at least one symptom of a disorder but who has not yet done so. Such individuals can be identified on the basis of risk factors that are known to correlate with the subsequent occurrence of the disease, such as the presence of a biomarker. Alternatively, prevention therapy can be administered as a prophylactic measure without prior identification of a risk factor. Delaying the onset of the at least one episode and/or symptom of a disorder can also be considered prevention or prophylaxis.

As used herein, the term “reacting”, “contacting”, or “treating” when describing a certain chemical reaction or process is used as known in the art and generally refers to the bringing together chemical reagents and/or intermediates in such a manner so as to allow their interaction at the molecular level to achieve a chemical or physical transformation. In some embodiments, the reacting involves two reagents, wherein one or more equivalents of second reagent are used with respect to the first reagent. The reacting steps of the processes described herein can be conducted for a time and under conditions suitable for preparing the identified product. Additional terms are also used herein solely to provide descriptive clarity between the different process steps and each of these terms have the same definition as described above. These additional terms include, “alkylating”, “cyclizing”, “deprotecting”, “reducing”, and “condensing”.

The term “solvate” as used herein refers to a solid-state form of a compound of the present invention or a pharmaceutically acceptable salt thereof which includes a stoichiometric or non stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

The term “subject”, as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate. In some embodiments, the subject is a human.

In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. In some embodiments, the subject has been identified or diagnosed as having congenital adrenal hyperplasia (CAH). In some embodiments, the subject is suspected of having CAH. In some embodiments, the subject has a clinical record indicating that the subject has CAH (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject.

As used herein, the term “substituted” refers to the replacement of at least one of hydrogen atom of a chemical group with a non-hydrogen substituent or group, the non-hydrogen substituent can be monovalent or divalent. When the chemical group or substituent is divalent, then it is understood that this group is further substituted with another substituent or group. When a chemical group herein is “substituted” it may have up to the full valance of substitution; for example, a methyl group can be substituted by 1, 2, or 3 substituents, a methylene group can be substituted by 1 or 2 substituents, a phenyl group can be substituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can be substituted by 1, 2, 3, 4, 5, 6, or 7 substituents, and the like. Likewise, “substituted with one or more substituents” refers to the substitution of a group substituted with one substituent up to the total number of substituents physically allowed by the group. It is understood that “optionally substituted” as used herein refers to the group being either “unsubstituted” or “substituted” with a group. Accordingly, when a group is “optionally substituted with one or more substituents”, it is understood that the group is either “unsubstituted” or “substituted” and when substituted, the group is substituted with one substituent up to the total number of substituents physically allowed by the group as described above. In some embodiments, a group can be “optionally substituted with one, two, three, or four substituents”. In some embodiments, a group can be “optionally substituted with one, two, or three substituents”. In some embodiments, a group can be “optionally substituted with one or two substituents”. In some embodiments, a group can be “optionally substituted with one substituent”. Further, when a group is substituted with more than one substituent, then the substituents can be identical, or they can be different. Examples of substituents include, without limitation, halogen, alkoxy, alkyl, haloalkyl, hydroxy, nitro.

As used herein, “treat”, or “treatment”, refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

The term “therapeutically effective amount” refers to the amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or an amount of a pharmaceutical composition comprising the compound of the invention or a pharmaceutically acceptable salt thereof, that elicits the biological or medicinal response in a tissue, system, animal, or human that is being sought by an individual, researcher, veterinarian, medical doctor, or other clinician or caregiver, which can include one or more of the following:

-   (1) preventing the disorder, for example, preventing a disease,     condition, or disorder in an individual who may be predisposed to     the disease, condition, or disorder but does not yet experience or     display the relevant pathology or symptomatology; -   (2) inhibiting the disorder, for example, inhibiting a disease,     condition, or disorder in an individual who is experiencing or     displaying the relevant pathology or symptomatology (i.e., arresting     further development of the pathology and/or symptomatology); and -   (3) ameliorating the disorder, for example, ameliorating a disease,     condition, or disorder in an individual who is experiencing or     displaying the relevant pathology or symptomatology (i.e., reversing     the pathology and/or symptomatology).

Crystalline Forms

The crystalline forms of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) and intermediates related thereto can be identified by their unique solid state signatures with respect to, for example, Differential Scanning Calorimetry (DSC), X-ray Powder Diffraction (XRPD), and other solid state methods. Further characterization with respect to water or solvent content of the crystalline forms can be gauged by any of the following methods for example, Thermogravimetric Analysis (TGA), DSC and the like.

For DSC, it is known that the temperatures observed for thermal events will depend upon sample purity and may also depend on the rate of temperature change, as well as sample preparation technique, and the instrument employed. Thus, the values reported herein relating to DSC thermograms can vary by plus or minus about 5° C. (i.e., ± about 5° C.). The values reported herein relating to DSC thermograms can also vary by plus or minus about 20 joules per gram (i.e., ± about 20 joules per gram).

For XRPD, the relative intensities of the peaks can vary, depending upon the sample preparation technique, the sample mounting procedure and the instrument employed. Moreover, instrument variation and other factors can often affect the 2θ values. Therefore, the peak assignments of diffraction patterns can vary by plus or minus about 0.2° (i.e., ± about 0.2°). For TGA, the temperature features reported herein can vary by plus or minus about 5° C. (i.e., ± about 5° C.). The TGA % weight changes reported herein over a specified temperature range can vary by plus or minus about 2% weight change (i.e., ± about 2% weight change) due to, for example, variations in sample quality and sample size. All X-ray powder diffraction patterns (diffractograms) were obtained using Cu-Ka radiation.

Further characterization with respect to hygroscopicity of the crystalline form can be gauged by, for example, Gravimetric Vapor Sorption (GVS). The GVS features reported herein can vary by plus or minus about 5% relative humidity (i.e., ± about 5% relative humidity). The GVS features reported herein can also vary by plus or minus about 2% weight change (i.e., ± about 2% weight change).

A. 4-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, Anhydrous Crystalline Form I)

One aspect of the present invention relates to a novel anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base) and processes related thereto.

A summary of representative physical properties for the anhydrous crystalline form are provided in Table 1 and Table 2.

TABLE 1 Compound 1 (Free Base, Anhydrous Form, Form I) PXRD FIG. 1 : Peaks at 25.7, 19.7, 14.3, 20.2, 26.8, 29.6, 22.3, and 43.5°2θ TGA FIG. 2 : Decrease in weight of about 0.2% out to about 125° C. DSC FIG. 2 : Endotherm extrapolated onset temperature: about 83.7° C. GVS FIG. 3 : The adsorption/desorption isotherm shows about 0.1% or less weight change from about 10% relative humidity (RH) to about 90% RH; and about 0.015% or less weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH.

Certain other XRPD peaks for the anhydrous form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base) are shown in Table 2 below.

TABLE 2 Selected X-Ray Powder Diffraction (XRPD) Peaks for Form I of Compound 1 (Free Base) 2-Theta Height (cps) 2-Theta Height (cps) 2-Theta Height (cps) 3.7 1367 23.9 40096 36.0 2386 6.0 54956 24.2 8183 36.1 19374 10.5 1411 25.7 28318 36.7 2685 11.9 38857 26.4 1402 36.9 1007 12.7 2962 26.8 12745 37.4 5567 13.9 7511 27.4 1756 37.9 1583 14.3 19162 27.9 2135 39.1 2220 15.3 633 28.7 8128 39.8 898 15.9 5554 29.6 9678 40.0 1084 16.8 5276 30.8 1608 40.7 2910 17.9 12355 31.1 3504 41.2 894 18.5 2151 31.7 2234 42.0 1390 19.7 23327 31.9 2063 42.4 1279 20.2 16234 33.3 1006 42.9 1844 20.9 8301 33.7 3078 43.5 8967 21.8 7076 34.3 981 43.6 5252 22.3 9288 34.6 1161 44.2 535 23.2 2553 35.4 1906 44.5 4977

The GVS profile (adsorption/desorption isotherm) for the anhydrous crystalline Form I of Compound 1 (free base) is shown in FIG. 3 . The corresponding data in tabular form is provided in Table 3, where there was substantially no weight change after a cycle from 10% RH to 90% RH and back to 10% RH.

TABLE 3 Relative Humidity (%) Phase Weight Change (%) 30 Adsorption 0.002407 50 Adsorption 0.005586 70 Adsorption 0.01094 90 Adsorption 0.02554 90 Desorption 0.02554 70 Desorption 0.01522 50 Desorption 0.008494 30 Desorption 0.003817

One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base). Anhydrous crystalline Form I of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base) refers to anhydrous crystalline form that contains 2% or less of water. In some embodiments, the anhydrous crystalline form contains 1% or less water. In some embodiments, the water content is determined by Karl Fischer (KF) analysis.

One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least three peaks, in terms of 2θ, selected from the group consisting of: 6.0° ± 0.2°, 11.9° ± 0.2°, 13.9° ± 0.2°, 14.3° ± 0.2°, 16.8° ± 0.2°, 17.9° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, 36.1° ± 0.2°, and 43.5° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising at least four peaks, in terms of 2θ, selected from the group consisting of: 6.0° ± 0.2°, 11.9° ± 0.2°, 13.9° ± 0.2°, 14.3° ± 0.2°, 16.8° ± 0.2°, 17.9° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, 36.1° ± 0.2°, and 43.5° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising at least five peaks, in terms of 2θ, selected from the group consisting of: 6.0° ± 0.2°, 11.9° ± 0.2°, 13.9° ± 0.2°, 14.3° ± 0.2°, 16.8° ± 0.2°, 17.9° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, 36.1° ± 0.2°, and 43.5° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising at least six peaks, in terms of 2θ, selected from the group consisting of: 6.0° ± 0.2°, 11.9° ± 0.2°, 13.9° ± 0.2°, 14.3° ± 0.2°, 16.8° ± 0.2°, 17.9° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, 36.1° ± 0.2°, and 43.5° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising at least seven peaks, in terms of 2θ, selected from the group consisting of: 6.0° ± 0.2°, 11.9° ± 0.2°, 13.9° ± 0.2°, 14.3° ± 0.2°, 16.8° ± 0.2°, 17.9° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, 36.1° ± 0.2°, and 43.5° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising at least eight peaks, in terms of 2θ, selected from the group consisting of: 6.0° ± 0.2°, 11.9° ± 0.2°, 13.9° ± 0.2°, 14.3° ± 0.2°, 16.8° ± 0.2°, 17.9° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, 36.1° ± 0.2°, and 43.5° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising at least nine peaks, in terms of 2θ, selected from the group consisting of: 6.0° ± 0.2°, 11.9° ± 0.2°, 13.9° ± 0.2°, 14.3° ± 0.2°, 16.8° ± 0.2°, 17.9° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, 36.1° ± 0.2°, and 43.5° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising at least ten peaks, in terms of 2θ, selected from the group consisting of: 6.0° ± 0.2°, 11.9° ± 0.2°, 13.9° ± 0.2°, 14.3° ± 0.2°, 16.8° ± 0.2°, 17.9° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, 36.1° ± 0.2°, and 43.5° ± 0.2°.

One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 14.3° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 19.7° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 25.7° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.3° ± 0.2°, and 25.7° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.3° ± 0.2°, and 19.7° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 19.7° ± 0.2°, and 25.7° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, and 25.7° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, and 25.7° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, and 29.6° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 22.3° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, and 29.6° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 22.3° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 29.6° ± 0.2°, and 43.5° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 22.3° ± 0.2°, 25.7° ± 0.2°, 24.2° ± 0.2°, 26.8° ± 0.2°, 29.6° ± 0.2°, and 43.5° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 22.3° ± 0.2°, 25.7° ± 0.2°, 24.2° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, and 43.5° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 25.7° ± 0.2°, 24.2° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, and 43.5° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern substantially as shown in FIG. 1 , wherein by ”substantially” is meant that the reported peaks can vary by about ± 0.2°2θ.

It is understood that peak intensities can vary from one diffractogram to another for the same crystalline form based on any number of factors that are known to those skilled in the art, such as, preferred orientation effects, preparation technique, the sample mounting procedure, the instrument employed, etc. In some instances, peak intensities can be rather dramatical. Accordingly, the diffraction peak intensities shown herein are illustrative and identical diffraction peak intensities are not necessarily required. One example is the XRPD for Form I shown in FIG. 7 showing substantially the same peak positions but dramatic peak intensity differences. One skilled in the art would understand that FIG. 1 and FIG. 7 are the XRPD’s for Form I, despite the differences in the peak intensities. Similarly, those skilled in the art would readily be capable of comparing the diffractograms provided herein with a diffractogram generated for an unknown crystal form and confirm whether the diffractogram is characterizing the same crystal form as provided herein or a different form.

One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an extrapolated onset temperature of about 81° C. to about 89.5° C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 82° C. to about 88° C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 82.5° C. to about 88.5° C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 83° C. to about 88° C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 83.5° C. to about 87.5° C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a differential scanning calorimetry thermogram substantially as shown in FIG. 2 , wherein by “substantially” is meant that the reported DSC features can vary by about ±5° C. and the reported DSC features can vary by about ± 20 joules per gram.

One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile showing about 1.0% or less weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile showing about 0.9% or less weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile showing about 0.7% or less weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile showing about 0.6% or less weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile showing about 0.5% or less weight loss out to about 125° C.

One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile showing about 0.05% to about 1.0% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile showing about 0.1% to about 0.9% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile showing about 0.1% to about 0.7% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile showing about 0.1% to about 0.6% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile showing about 0.1% to about 0.4% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile substantially as shown in FIG. 2 , wherein by “substantially” is meant that the reported TGA features can vary by about ± 5° C., and the reported TGA features can vary by about ± 2% weight change (i.e., ± about 2% weight change).

One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.015% or less weight change after an adsorption/desorption cycle from 10% relative humidity (RH) to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile showing about 0.01% or less weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile showing about 0.008% or less weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile showing about 0.005% or less weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile showing about 0.003% or less weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile showing substantially no weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH.

One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.1% or less weight change from about 10% relative humidity (RH) to about 90% RH; and about 0.015% or less weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile showing about 0.08% or less weight change from about 10% relative humidity (RH) to about 90% RH; and about 0.01% or less weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile showing about 0.05% or less weight change from about 10% relative humidity (RH) to about 90% RH; and about 0.008% or less weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile showing about 0.04% or less weight change from about 10% RH to about 90% RH; and about 0.005% or less weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile showing about 0.03% or less weight change from about 10% RH to about 90% RH; and about 0.003% or less weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile showing about 0.2% or less weight change from about 10% RH to about 90% RH; and substantially no weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile substantially as shown in FIG. 3 , wherein “substantially” is meant that the reported GVS features can vary by plus or minus about 5% relative humidity (i.e., ± about 5% relative humidity) and also vary by plus or minus about 2% weight change (i.e., ± about 2% weight change).

One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern comprising at least three peaks,     in terms of 2θ, selected from the group consisting of: 6.0° ± 0.2°,     11.9° ± 0.2°, 13.9° ± 0.2°, 14.3° ± 0.2°, 16.8° ± 0.2°, 17.9° ±     0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3°     ± 0.2°, 23.2° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°,     26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, 36.1° ± 0.2°, and 43.5° ±     0.2°; -   a differential scanning calorimetry thermogram comprising an     endotherm with an extrapolated onset temperature of about 81° C. to     about 89.5° C.; -   a thermogravimetric analysis profile showing about 0.05% to about     1.0% weight loss out to about 125° C.; and/or -   a gravimetric vapor sorption profile showing about 0.015% or less     weight change after an adsorption/desorption cycle from 10% RH to     90% RH and back to 10% RH.

One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern comprising peaks, in terms of     2θ,at 14.3° ± 0.2°, 19.7° ± 0.2°, and 25.7° ± 0.2°; -   a differential scanning calorimetry thermogram comprising an     endotherm with an extrapolated onset temperature of about 82.5° C.     to about 88.5° C.; -   a thermogravimetric analysis profile showing about 0.7% or less     weight loss out to about 125° C.; and/or -   a gravimetric vapor sorption profile showing about 0.005% or less     weight change after an adsorption/desorption cycle from 10% RH to     90% RH and back to 10% RH.

One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern comprising peaks, in terms of     2θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 22.3° ± 0.2°, 25.7°     ± 0.2°, 26.8° ± 0.2°, 29.6° ± 0.2°, and 43.5° ± 0.2°; -   a differential scanning calorimetry thermogram comprising an     endotherm with an extrapolated onset temperature of about 83° C. to     about 88° C.; -   a thermogravimetric analysis profile showing about 0.5% or less     weight loss out to about 125° C.; and/or -   a gravimetric vapor sorption profile showing about 0.003% or less     weight change after an adsorption/desorption cycle from 10% RH to     90% RH and back to 10% RH.

One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern substantially as shown in FIG. 1     ; -   a differential scanning calorimetry thermogram substantially as     shown in FIG. 2 ; -   a thermogravimetric analysis profile substantially as shown in FIG.     2 ; and/or -   a gravimetric vapor sorption profile substantially as shown in FIG.     3 .

In some embodiments, the anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base) can be isolated as the crystalline form described herein, with a crystalline purity of at least about 75% by weight. In some embodiments, about 80% by weight. In some embodiments, about 85% by weight. In some embodiments, about 90% by weight. In some embodiments, about 95% by weight. In some embodiments, about 96% by weight. In some embodiments, about 97% by weight. In some embodiments, about 98% by weight. In some embodiments, about 99% by weight.

The manufacturing batches of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base) have been prepared with the following particle size distribution characterization, as shown in Table 4.

TABLE 4 Particle size distribution Batch 1 Batch 2 Batch 3 Batch 4 D10 21 µM 17 µM 16 µM 14 µM D50 129 µM 123 µM 107 µM 107 µM D90 468 µM 335 µM 320 µM 327 µM

In some embodiments, the anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base) has a particle size D10 of about 8 µM to about 35 µM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D10 of about 10 µM to about 30 µM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D10 of about 10 µM to about 27 µM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D10 of about 12 µM to about 25 µM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D10 of about 12 µM to about 23 µM.

In some embodiments, the anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base) has a particle size D50 of about 80 µM to about 150 µM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D50 of about 90 µM to about 145 µM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D50 of about 100 µM to about 140 µM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D50 of about 100 µM to about 135 µM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D50 of about 105 µM to about 130 µM.

In some embodiments, the anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base) has a particle size D90 of about 280 µM to about 490 µM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D90 of about 290 µM to about 485 µM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D90 of about 300 µM to about 480 µM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D90 of about 305 µM to about 475 µM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D90 of about 310 µM to about 470 µM.

B. (S)(2-Chloromethoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoromethylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A, Anhydrous Crystalline Form)

One aspect of the present invention relates to a novel anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) and processes related thereto.

A summary of representative physical properties for the anhydrous crystalline form are below in Table 5 and Table 6.

TABLE 5 Compound 9A (Anhydrous Form) PXRD FIG. 9 : Peaks at 8.3, 15.2, 16.7, 18.4, 19.0, 19.8, 20.7, 21.5, 23.1, and 25.7°2θ TGA FIG. 10 : Decrease in weight of about 0.2% out to about 125° C. DSC FIG. 10 : Endotherm extrapolated onset temperature: about 132.5° C.

Certain other XRPD peaks for the crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) are shown in Table 6 below.

TABLE 6 2-Theta Height (cps) 2-Theta Height (cps) 2-Theta Height (cps) 6.9 3643 24.7 2987 35.6 646 8.3 10896 25.2 5834 36 975 11.5 6618 25.7 20895 36.7 694 12 2294 26 3751 37.4 1490 12.9 1433 26.2 6435 37.8 1794 13.9 3413 26.9 5510 38 3987 14.7 1158 27.1 5737 38.6 4047 15.2 13136 28 5154 39.5 1217 15.5 8199 28.4 744 39.7 1138 16.7 12477 28.9 3802 40.1 2059 18.4 19226 29.8 1824 40.6 377 19 18818 30.5 2030 41.7 532 19.8 11522 31 1030 42 2005 20.7 10872 31.4 2970 42.7 589 21.5 10898 32.1 1687 43.3 794 22.1 1251 32.6 1628 43.6 1946 22.9 5163 33.7 2844 43.9 733 23.1 17329 34.5 497

One aspect of the present invention relates to a crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A). In some embodiments, the crystal form is an anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A). An anhydrous crystalline form refers to a crystalline form that contains 2% or less of water. In some embodiments, the anhydrous crystalline form contains 1% or less water. In some embodiments, the water content is determined by Karl Fischer (KF) analysis.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least three peaks, in terms of 2θ, selected from the group consisting of: 8.3° ± 0.2°, 11.5° ± 0.2°, 15.2° ± 0.2°, 15.5° ± 0.2°, 16.7° ± 0.2°, 18.4° ± 0.2°, 19.0° ± 0.2°, 19.8° ± 0.2°, 20.7° ± 0.2°, 21.5° ± 0.2°, 23.1° ± 0.2°, 25.2° ± 0.2°, 25.7° ± 0.2°, 26.2° ± 0.2°, 26.9° ± 0.2°, 27.1°± 0.2°, and 28.0° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least four peaks, in terms of 2θ,selected from the group consisting of: 8.3° ± 0.2°, 11.5° ± 0.2°, 15.2° ± 0.2°, 15.5° ± 0.2°, 16.7° ± 0.2°, 18.4° ± 0.2°, 19.0° ± 0.2°, 19.8° ± 0.2°, 20.7° ± 0.2°, 21.5° ± 0.2°, 23.1° ± 0.2°, 25.2° ± 0.2°, 25.7° ± 0.2°, 26.2° ± 0.2°, 26.9° ± 0.2°, 27.1° ± 0.2°, and 28.0° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least five peaks, in terms of 2θ, selected from the group consisting of: 8.3° ± 0.2°, 11.5° ± 0.2°, 15.2° ± 0.2°, 15.5° ± 0.2°, 16.7° ± 0.2°, 18.4° ± 0.2°, 19.0° ± 0.2°, 19.8° ± 0.2°, 20.7° ± 0.2°, 21.5° ± 0.2°, 23.1° ± 0.2°, 25.2° ± 0.2°, 25.7° ± 0.2°, 26.2° ± 0.2°, 26.9° ± 0.2°, 27.1° ± 0.2°, and 28.0° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least six peaks, in terms of 2θ, selected from the group consisting of: 8.3° ± 0.2°, 11.5° ± 0.2°, 15.2° ± 0.2°, 15.5° ± 0.2°, 16.7° ± 0.2°, 18.4° ± 0.2°, 19.0° ± 0.2°, 19.8° ± 0.2°, 20.7° ± 0.2°, 21.5° ± 0.2°, 23.1° ± 0.2°, 25.2° ± 0.2°, 25.7° ± 0.2°, 26.2° ± 0.2°, 26.9° ± 0.2°, 27.1° ± 0.2°, and 28.0° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least seven peaks, in terms of 2θ,selected from the group consisting of: 8.3° ± 0.2°, 11.5° ± 0.2°, 15.2° ± 0.2°, 15.5° ± 0.2°, 16.7° ± 0.2°, 18.4° ± 0.2°, 19.0° ± 0.2°, 19.8° ± 0.2°, 20.7° ± 0.2°, 21.5° ± 0.2°, 23.1° ± 0.2°, 25.2° ± 0.2°, 25.7° ± 0.2°, 26.2° ± 0.2°, 26.9° ± 0.2°, 27.1° ± 0.2°, and 28.0° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least eight peaks, in terms of 2θ, selected from the group consisting of: 8.3° ± 0.2°, 11.5° ± 0.2°, 15.2° ± 0.2°, 15.5° ± 0.2°, 16.7° ± 0.2°, 18.4° ± 0.2°, 19.0° ± 0.2°, 19.8° ± 0.2°, 20.7° ± 0.2°, 21.5° ± 0.2°, 23.1° ± 0.2°, 25.2° ± 0.2°, 25.7° ± 0.2°, 26.2° ± 0.2°, 26.9° ± 0.2°, 27.1° ± 0.2°, and 28.0° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least nine peaks, in terms of 2θ, selected from the group consisting of: 8.3° ± 0.2°, 11.5° ± 0.2°, 15.2° ± 0.2°, 15.5° ± 0.2°, 16.7° ± 0.2°, 18.4° ± 0.2°, 19.0° ± 0.2°, 19.8° ± 0.2°, 20.7° ± 0.2°, 21.5° ± 0.2°, 23.1° ± 0.2°, 25.2° ± 0.2°, 25.7° ± 0.2°, 26.2° ± 0.2°, 26.9° ± 0.2°, 27.1° ± 0.2°, and 28.0° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least ten peaks, in terms of 2θ, selected from the group consisting of: 8.3° ± 0.2°, 11.5° ± 0.2°, 15.2° ± 0.2°, 15.5° ± 0.2°, 16.7° ± 0.2°, 18.4° ± 0.2°, 19.0° ± 0.2°, 19.8° ± 0.2°, 20.7° ± 0.2°, 21.5° ± 0.2°, 23.1° ± 0.2°, 25.2° ± 0.2°, 25.7° ± 0.2°, 26.2° ± 0.2°, 26.9° ± 0.2°, 27.1° ± 0.2°, and 28.0° ± 0.2°.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 25.7° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 18.4° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 19.0° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 18.4° ± 0.2° and 19.0° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 18.4° ± 0.2° and 25.7° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 19.0° ± 0.2° and 25.7° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 18.4° ± 0.2°, 19.0° ± 0.2°, and 25.7°± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 18.4° ± 0.2°, 19.0° ± 0.2°, 23.1° ± 0.2°, and 25.7° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 15.2° ± 0.2°, 18.4° ± 0.2°, 19.0° ± 0.2°, 23.1° ± 0.2°, and 25.7° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 15.2° ± 0.2°, 16.7° ± 0.2°, 18.4° ± 0.2°, 19.0° ± 0.2°, 19.8° ± 0.2°, 23.1° ± 0.2°, and 25.7° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 15.2° ± 0.2°, 16.7° ± 0.2°, 18.4° ± 0.2°, 19.0° ± 0.2°, 19.8° ± 0.2°, 21.5° ± 0.2°, 23.1° ± 0.2°, and 25.7° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 8.3° ± 0.2°, 15.2° ± 0.2°, 16.7° ± 0.2°, 18.4° ± 0.2°, 19.0° ± 0.2°, 19.8° ± 0.2°, 21.5° ± 0.2°, 23.1° ± 0.2°, and 25.7° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 8.3° ± 0.2°, 15.2° ± 0.2°, 16.7° ± 0.2°, 18.4° ± 0.2°, 19.0° ± 0.2°, 19.8° ± 0.2°, 20.7° ± 0.2°, 21.5° ± 0.2°, 23.1° ± 0.2°, and 25.7° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 8.3° ± 0.2°, 11.5° ± 0.2°, 15.2° ± 0.2°, 15.5° ± 0.2°, 16.7° ± 0.2°, 18.4° ± 0.2°, 19.0° ± 0.2°, 19.8° ± 0.2°, 20.7° ± 0.2°, 21.5° ± 0.2°, 23.1° ± 0.2°, and 25.7° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern substantially as shown in FIG. 9 , wherein by “substantially” is meant that the reported peaks can vary by about ± 0.2°2θ.

It is understood that peak intensities can vary from one diffractogram to another for the same crystalline form based on any number of factors that are known to those skilled in the art, such as, preferred orientation effects, preparation technique, the sample mounting procedure, the instrument employed, etc. In some instances, peak intensities can be rather dramatical. Accordingly, the diffraction peak intensities shown herein are illustrative and identical diffraction peak intensities are not necessarily required. One skilled in the art would readily be capable of comparing the diffractogram provided herein with a diffractogram generated for an unknown crystal form and confirm whether the diffractogram is characterizing the same crystal form as provided herein or a different form.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A), wherein the anhydrous crystalline form has a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an extrapolated onset temperature of about 129° C. to about 136° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 130.5° C. to about 135.5° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 131° C. to about 134° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 131.5° C. to about 133.5° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 132° C. to about 133° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram substantially as shown in FIG. 10 , wherein by “substantially” is meant that the reported DSC features can vary by about ± 5° C. and the reported DSC features can vary by about ± 20 joules per gram.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile showing about 1.0% or less weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.7% or less weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.4% or less weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.2% or less weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.15% or less weight loss out to about 125° C.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile showing about 0.05% to about 1.0% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.05% to about 0.7% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.05% to about 0.4% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.05% to about 0.2% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.05% to about 0.15% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile substantially as shown in FIG. 10 , wherein by “substantially” is meant that the reported TGA features can vary by about ± 5° C., and the reported TGA features can vary by about ± 2% weight change (i.e., ± about 2% weight change).

One aspect of the present invention relates to an anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern comprising at least three peaks,     in terms of 2θ, selected from the group consisting of: 8.3° ± 0.2°,     11.5° ± 0.2°, 15.2° ± 0.2°, 15.5° ± 0.2°, 16.7° ± 0.2°, 18.4° ±     0.2°, 19.0° ± 0.2°, 19.8° ± 0.2°, 20.7° ± 0.2°, 21.5° ± 0.2°, 23.1°     ± 0.2°,25.2° ± 0.2°, 25.7° ± 0.2°, 26.2° ± 0.2°, 26.9° ± 0.2°, 27.1°     ± 0.2°, and 28.0° ± 0.2°; -   a differential scanning calorimetry thermogram comprising an     endotherm with an extrapolated onset temperature of about 129° C. to     about 136° C.; and/or -   a thermogravimetric analysis profile showing about 0.05% to about     1.0% weight loss out to about 125° C.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern comprising peaks, in terms of     2θ, at 18.4° ± 0.2°, 19.0° ± 0.2°, and 25.7° ± 0.2°; -   a differential scanning calorimetry thermogram comprising an     endotherm with an extrapolated onset temperature of about 131° C. to     about 134° C.; and/or -   a thermogravimetric analysis profile showing about 0.7% or less     weight loss out to about 125° C.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern comprising peaks, in terms of     2θ, at 8.3° ± 0.2°, 15.2° ± 0.2°, 16.7° ± 0.2°, 18.4° ± 0.2°, 19.0°     ± 0.2°, 19.8° ± 0.2°, 21.5° ± 0.2°, 23.1° ± 0.2°, and 25.7° ± 0.2°; -   a differential scanning calorimetry thermogram comprising an     endotherm with an extrapolated onset temperature of about 132° C. to     about 133° C.; and/or -   a thermogravimetric analysis profile showing about 0.4% or less     weight loss out to about 125° C.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern substantially as shown in FIG. 9     ; -   a differential scanning calorimetry thermogram substantially as     shown in FIG. 10 ; and/or -   a thermogravimetric analysis profile substantially as shown in FIG.     10 .

In some embodiments, the anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) can be isolated as the crystalline form described herein, with a crystalline purity of at least about 75% by weight. In some embodiments, about 80% by weight. In some embodiments, about 85% by weight. In some embodiments, about 90% by weight. In some embodiments, about 95% by weight. In some embodiments, about 96% by weight. In some embodiments, about 97% by weight. In some embodiments, about 98% by weight. In some embodiments, about 99% by weight.

C. 1-Chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one(Compound 8A, Crystalline Form)

One aspect of the present invention relates to a novel anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A) and processes related thereto.

A summary of representative physical properties for the crystalline form are provided in Table 7 and Table 8.

TABLE 7 Compound 8A (Anhydrous Form) PXRD FIG. 11 : Peaks at 12.6, 18.9, 21.3, 22.2, 24.9, 26.7, 27.8, 34.8, and 42.3 °2θ TGA FIG. 12 : Decrease in weight of about 0.3% out to about 125° C. DSC FIG. 12 : Endotherm extrapolated onset temperature: about 73.1° C.

Certain other XRPD peaks for the crystalline anhydrous form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A) are shown in Table 8 below.

TABLE 8 2-Theta Height (cps) 2-Theta Height (cps) 2-Theta Height (cps) 8.3 767 24.9 46622 35.7 1131 12.6 6589 25.5 6199 35.9 1679 13.8 6107 25.9 1137 36.5 1158 16.4 3455 26.7 11565 36.8 1086 17.1 3934 27.5 7283 37.3 874 17.7 1196 27.8 11083 38.2 2154 18.9 8251 29.4 1033 39.2 4626 19.3 6016 30.8 2182 40.2 878 19.8 546 32.3 2349 40.9 1077 20.2 1162 33.0 3021 41.9 2734 21.3 7007 33.4 3388 42.3 13647 22.2 6456 33.6 2842 42.7 3438 22.5 1290 34.0 1033 43.2 819 22.7 352 34.8 11013 43.8 1003 23.3 1823 35.4 1250 44.3 3522

One aspect of the present invention relates to a crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A). In some embodiments, the crystal form is an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A). An anhydrous crystalline form refers to a crystalline form that contains 2% or less of water. In some embodiments, the anhydrous crystalline form contains 1% or less water. In some embodiments, the water content is determined by Karl Fischer (KF) analysis.

One aspect of the present invention relates to an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least three peaks, in terms of 2θ, selected from the group consisting of: 12.6° ± 0.2°, 13.8° ± 0.2°, 18.9° ± 0.2°, 19.3° ± 0.2°, 21.3° ± 0.2°, 22.2° ± 0.2°, 24.9° ± 0.2°, 25.5° ± 0.2°, 26.7° ± 0.2°, 27.5° ± 0.2°, 27.8° ± 0.2°, 34.8° ± 0.2°, 39.2° ± 0.2°, and 42.3° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least four peaks, in terms of 2θ, selected from the group consisting of: 12.6° ± 0.2°, 13.8° ± 0.2°, 18.9° ± 0.2°, 19.3° ± 0.2°, 21.3° ± 0.2°, 22.2° ± 0.2°, 24.9° ± 0.2°, 25.5° ± 0.2°, 26.7° ± 0.2°, 27.5° ± 0.2°, 27.8° ± 0.2°, 34.8° ± 0.2°, 39.2° ± 0.2°, and 42.3° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least five peaks, in terms of 2θ, selected from the group consisting of: 12.6° ± 0.2°, 13.8° ± 0.2°, 18.9° ± 0.2°, 19.3° ± 0.2°, 21.3° ± 0.2°, 22.2° ± 0.2°, 24.9° ± 0.2°, 25.5° ± 0.2°, 26.7° ± 0.2°, 27.5° ± 0.2°, 27.8° ± 0.2°, 34.8° ± 0.2°, 39.2° ± 0.2°, and 42.3° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least six peaks, in terms of 2θ, selected from the group consisting of: 12.6° ± 0.2°, 13.8° ± 0.2°, 18.9° ± 0.2°, 19.3° ± 0.2°, 21.3° ± 0.2°, 22.2° ± 0.2°, 24.9° ± 0.2°, 25.5° ± 0.2°, 26.7° ± 0.2°, 27.5° ± 0.2°, 27.8° ± 0.2°, 34.8° ± 0.2°, 39.2° ± 0.2°, and 42.3° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least seven peaks, in terms of 2θ, selected from the group consisting of: 12.6° ± 0.2°, 13.8° ± 0.2°, 18.9° ± 0.2°, 19.3° ± 0.2°, 21.3° ± 0.2°, 22.2° ± 0.2°, 24.9° ± 0.2°, 25.5° ± 0.2°, 26.7° ± 0.2°, 27.5° ± 0.2°, 27.8° ± 0.2°, 34.8° ± 0.2°, 39.2° ± 0.2°, and 42.3° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least eight peaks, in terms of 2θ, selected from the group consisting of: 12.6° ± 0.2°, 13.8° ± 0.2°, 18.9° ± 0.2°, 19.3° ± 0.2°, 21.3° ± 0.2°, 22.2° ± 0.2°, 24.9° ± 0.2°, 25.5° ± 0.2°, 26.7° ± 0.2°, 27.5° ± 0.2°, 27.8° ± 0.2°, 34.8° ± 0.2°, 39.2° ± 0.2°, and 42.3° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least nine peaks, in terms of 2θ, selected from the group consisting of: 12.6° ± 0.2°, 13.8° ± 0.2°, 18.9° ± 0.2°, 19.3° ± 0.2°, 21.3° ± 0.2°, 22.2° ± 0.2°, 24.9° ± 0.2°, 25.5° ± 0.2°, 26.7° ± 0.2°, 27.5° ± 0.2°, 27.8° ± 0.2°, 34.8° ± 0.2°, 39.2° ± 0.2°, and 42.3° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least ten peaks, in terms of 2θ, selected from the group consisting of: 12.6° ± 0.2°, 13.8° ± 0.2°, 18.9° ± 0.2°, 19.3° ± 0.2°, 21.3° ± 0.2°, 22.2° ± 0.2°, 24.9° ± 0.2°, 25.5° ± 0.2°, 26.7° ± 0.2°, 27.5° ± 0.2°, 27.8° ± 0.2°, 34.8° ± 0.2°, 39.2° ± 0.2°, and 42.3° ± 0.2°.

One aspect of the present invention relates to an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms 2θ, at 24.9° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 24.9° ± 0.2° and 26.7° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 24.9° ± 0.2° and 27.8° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 24.9° ± 0.2° and 34.8° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 24.9° ± 0.2° and 42.3° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 18.9° ± 0.2°, 24.9° ± 0.2°, and 26.7° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 18.9° ± 0.2°, 24.9° ± 0.2°, and 27.8° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 18.9° ± 0.2°, 24.9° ± 0.2°, and 34.8° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 18.9° ± 0.2°, 24.9° ± 0.2°, and 42.3° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 24.9° ± 0.2°, 26.7° ± 0.2°, 27.8° ± 0.2°, 34.8° ± 0.2°, and 42.3° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 18.9° ± 0.2°, 24.9° ± 0.2°, 26.7° ± 0.2°, 27.8° ± 0.2°, 34.8° ± 0.2°, and 42.3° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 18.9° ± 0.2°, 24.9° ± 0.2°, 26.7° ± 0.2°, 27.5° ± 0.2°, 27.8° ± 0.2°, 34.8° ± 0.2°, and 42.3° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 18.9° ± 0.2°, 21.3° ± 0.2°, 24.9° ± 0.2°, 26.7° ± 0.2°, 27.5° ± 0.2°, 27.8° ± 0.2°, 34.8° ± 0.2°, and 42.3° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 12.6° ± 0.2°, 18.9° ± 0.2°, 21.3° ± 0.2°, 24.9° ± 0.2°, 26.7° ± 0.2°, 27.8° ± 0.2°, 34.8° ± 0.2°, and 42.3° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 12.6° ± 0.2°, 18.9° ± 0.2°, 21.3° ± 0.2°, 24.9° ± 0.2°, 26.7° ± 0.2°, 27.5° ± 0.2°, 27.8° ± 0.2°, 34.8° ± 0.2°, and 42.3° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 12.6° ± 0.2°, 18.9° ± 0.2°, 21.3° ± 0.2°, 22.2° ± 0.2°, 24.9° ± 0.2°, 26.7° ± 0.2°, 27.5° ± 0.2°, 27.8° ± 0.2°, 34.8° ± 0.2°, and 42.3° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 12.6° ± 0.2°, 18.9° ± 0.2°, 21.3° ± 0.2°, 22.2° ± 0.2°, 24.9° ± 0.2°, 25.5° ± 0.2°, 26.7° ± 0.2°, 27.5° ± 0.2°, 27.8° ± 0.2°, 34.8° ± 0.2°, and 42.3° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 12.6° ± 0.2°, 13.8° ± 0.2°, 18.9° ± 0.2°, 21.3° ± 0.2°, 22.2° ± 0.2°, 24.9° ± 0.2°, 25.5° ± 0.2°, 26.7° ± 0.2°, 27.5° ± 0.2°, 27.8° ± 0.2°, 34.8° ± 0.2°, and 42.3° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern substantially as shown in FIG. 11 , wherein by “substantially” is meant that the reported peaks can vary by about ± 0.2°2θ.

It is understood that peak intensities can vary from one diffractogram to another for the same crystalline form based on any number of factors that are known to those skilled in the art, such as, preferred orientation effects, preparation technique, the sample mounting procedure, the instrument employed, etc. In some instances, peak intensities can be rather dramatical. Accordingly, the diffraction peak intensities shown herein are illustrative and identical diffraction peak intensities are not necessarily required. One skilled in the art would readily be capable of comparing the diffractogram provided herein with a diffractogram generated for an unknown crystal form and confirm whether the diffractogram is characterizing the same crystal form as provided herein or a different form.

One aspect of the present invention relates to an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A), wherein the anhydrous crystalline form has a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an extrapolated onset temperature of about 70.5° C. to about 75.5° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 71° C. to about 75° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 71.5° C. to about 74.5° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 72° C. to about 74° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 72.5° C. to about 73.5° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram substantially as shown in FIG. 12 , wherein by “substantially” is meant that the reported DSC features can vary by about ±5° C. and the reported DSC features can vary by about ± 20 joules per gram.

One aspect of the present invention relates to an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile showing about 1.0% or less weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.8% or less weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.5% or less weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.4% or less weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.35% or less weight loss out to about 125° C.

One aspect of the present invention relates to an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile showing about 0.1% to about 1.0% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.15% to about 0.8% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.2% to about 0.5% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.25% to about 0.4% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.3% to about 0.35% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile substantially as shown in FIG. 12 , wherein by “substantially” is meant that the reported TGA features can vary by about ± 5° C., and the reported TGA features can vary by about ± 2% weight change (i.e., ± about 2% weight change).

One aspect of the present invention relates to an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern comprising at least three peaks,     in terms of 2θ, selected from the group consisting of: 12.6° ± 0.2°,     13.8° ± 0.2°, 18.9° ± 0.2°, 19.3° ± 0.2°, 21.3° ± 0.2°, 22.2° ±     0.2°, 24.9° ± 0.2°, 25.5° ± 0.2°, 26.7° ± 0.2°, 27.5° ± 0.2°, 27.8°     ± 0.2°, 34.8° ± 0.2°, 39.2° ± 0.2°, and 42.3° ± 0.2°; -   a differential scanning calorimetry (DSC) thermogram comprising an     endotherm with an extrapolated onset temperature of about 70.5° C.     to about 75.5° C.; and/or -   a thermogravimetric analysis (TGA) profile showing about 0.1% to     about 1.0% weight loss out to about 125° C.

One aspect of the present invention relates to an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern comprising peaks, in terms of     2θ, at 18.9° ± 0.2°, 24.9° ± 0.2°, 26.7° ± 0.2°, 27.8° ± 0.2°, 34.8°     ± 0.2°, and 42.3° ± 0.2°; -   a differential scanning calorimetry thermogram comprising an     endotherm with an extrapolated onset temperature of about 71.5° C.     to about 74.5° C.; and/or -   a thermogravimetric analysis profile showing about 1.0% or less     weight loss out to about 125° C.

One aspect of the present invention relates to an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern comprising peaks, in terms of     2θ, at 12.6° ± 0.2°, 18.9° ± 0.2°, 21.3° ± 0.2°, 24.9° ± 0.2°, 26.7°     ± 0.2°, 27.8° ± 0.2°, 34.8° ± 0.2°, and 42.3° ± 0.2°; -   a differential scanning calorimetry thermogram comprising an     endotherm with an extrapolated onset temperature of about 72.5° C.     to about 73.5° C.; and/or -   a thermogravimetric analysis profile showing about 0.5% or less     weight loss out to about 125° C.

One aspect of the present invention relates to an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern substantially as shown in FIG.     11 ; -   a differential scanning calorimetry thermogram substantially as     shown in FIG. 12 ; and/or -   a thermogravimetric analysis profile substantially as shown in FIG.     12 .

In some embodiments, the anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A) can be isolated as the crystalline form described herein, with a crystalline purity of at least about 75% by weight. In some embodiments, about 80% by weight. In some embodiments, about 85% by weight. In some embodiments, about 90% by weight. In some embodiments, about 95% by weight. In some embodiments, about 96% by weight. In some embodiments, about 97% by weight. In some embodiments, about 98% by weight. In some embodiments, about 99% by weight.

D. (S)Cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, Hydrochloride Salt, Crystalline Form)

One aspect of the present invention relates to a novel anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt) and processes related thereto.

A summary of representative physical properties for the crystalline form are provided in Table 9 and Table 10.

TABLE 9 Compound 6A, HCl Salt PXRD FIG. 13 : Peaks at 15.3, 20.5, 21.1, 21.5, 23.2, 23.6, 24.3, and 29.5°2θ TGA FIG. 14 : Decrease in weight of about 0.3% out to about 125° C. DSC FIG. 14 : Endotherm extrapolated onset temperature: about 159.5° C.

Certain other XRPD peaks for the crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt) are shown in Table 10 below.

TABLE 10 2-Theta Height (cps) 2-Theta Height (cps) 2-Theta Height (cps) 3.9 956 19.7 1903 27.5 1009 5.5 1646 20.5 13009 27.9 480 6.2 1526 21.1 9405 29.2 805 6.8 1657 21.5 3420 29.5 4775 9.1 303 22.3 2642 29.8 2679 12.4 1625 22.8 1094 30.6 547 13.7 2538 23.2 4031 32.2 577 14.8 2742 23.6 3439 34.2 444 15.3 3077 23.9 2863 35.0 1278 16.2 1629 24.3 5761 36.1 1130 17.2 732 24.9 1388 37.0 839 18.7 1236 25.3 404 38.1 897 19.0 364 26.7 397 39.4 517

One aspect of the present invention relates to a crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt). In some embodiments, the crystal form is an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt). An anhydrous crystalline form refers to a crystalline form that contains 2% or less of water. In some embodiments, the anhydrous crystalline form contains 1% or less water. In some embodiments, the water content is determined by Karl Fischer (KF) analysis.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least three peaks, in terms of 2θ, selected from the group consisting of: 13.7° ± 0.2°, 14.8° ± 0.2°, 15.3° ± 0.2°, 20.5° ± 0.2°, 21.1° ± 0.2°, 21.5° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.6° ± 0.2°, 24.3° ± 0.2°, 29.5° ± 0.2°, and 29.8° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least four peaks, in terms of 2θ, selected from the group consisting of: 13.7° ± 0.2°, 14.8° ± 0.2°, 15.3° ± 0.2°, 20.5° ± 0.2°, 21.1° ± 0.2°, 21.5° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.6° ± 0.2°, 24.3° ± 0.2°, 29.5° ± 0.2°, and 29.8° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least five peaks, in terms of 2θ, selected from the group consisting of: 13.7° ± 0.2°, 14.8° ± 0.2°, 15.3° ± 0.2°, 20.5° ± 0.2°, 21.1° ± 0.2°, 21.5° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.6° ± 0.2°, 24.3° ± 0.2°, 29.5° ± 0.2°, and 29.8° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least six peaks, in terms of 2θ, selected from the group consisting of: 13.7° ± 0.2°, 14.8° ± 0.2°, 15.3° ± 0.2°, 20.5° ± 0.2°, 21.1° ± 0.2°, 21.5° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.6° ± 0.2°, 24.3° ± 0.2°, 29.5° ± 0.2°, and 29.8° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least seven peaks, in terms of 2θ, selected from the group consisting of: 13.7° ± 0.2°, 14.8° ± 0.2°, 15.3° ± 0.2°, 20.5° ± 0.2°, 21.1° ± 0.2°, 21.5° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.6° ± 0.2°, 24.3° ± 0.2°, 29.5° ± 0.2°, and 29.8° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least eight peaks, in terms of 2θ, selected from the group consisting of: 13.7° ± 0.2°, 14.8° ± 0.2°, 15.3° ± 0.2°, 20.5° ± 0.2°, 21.1° ± 0.2°, 21.5° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.6° ± 0.2°, 24.3° ± 0.2°, 29.5° ± 0.2°, and 29.8° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least nine peaks, in terms of 2θ, selected from the group consisting of: 13.7° ± 0.2°, 14.8° ± 0.2°, 15.3° ± 0.2°, 20.5° ± 0.2°, 21.1° ± 0.2°, 21.5° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.6° ± 0.2°, 24.3° ± 0.2°, 29.5° ± 0.2°, and 29.8° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least ten peaks, in terms of 2θ, selected from the group consisting of: 13.7° ± 0.2°, 14.8° ± 0.2°, 15.3° ± 0.2°, 20.5° ± 0.2°, 21.1° ± 0.2°, 21.5° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.6° ± 0.2°, 24.3° ± 0.2°, 29.5° ± 0.2°, and 29.8° ± 0.2°.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 20.5° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 21.1° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 24.3° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 20.5° ± 0.2° and 21.1° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 20.5° ± 0.2° and 24.3° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 21.1° ± 0.2° and 24.3° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 20.5° ± 0.2°, 21.1° ± 0.2°, and 24.3° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 20.5° ± 0.2°, 21.1° ± 0.2°, 24.3° ± 0.2°, and 29.5° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 20.5° ± 0.2°, 21.1° ± 0.2°, 23.2° ± 0.2°, and 24.3° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 20.5° ± 0.2°, 21.1° ± 0.2°, 23.2° ± 0.2°, 24.3° ± 0.2°, and 29.5° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 20.5° ± 0.2°, 21.1° ± 0.2°, 23.2° ± 0.2°, 23.6° ± 0.2°, 24.3° ± 0.2°, and 29.5° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 20.5° ± 0.2°, 21.1° ± 0.2°, 21.5° ± 0.2°, 23.2° ± 0.2°, 24.3° ± 0.2°, and 29.5° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 20.5° ± 0.2°, 21.1° ± 0.2°, 21.5° ± 0.2°, 23.2° ± 0.2°, 23.6° ± 0.2°, 24.3° ± 0.2°, and 29.5° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 20.5° ± 0.2°, 21.1° ± 0.2°, 24.3° ± 0.2°, 29.5° ± 0.2°, 23.2° ± 0.2°, 15.3° ± 0.2°, and 14.8° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 15.3° ± 0.2°, 20.5° ± 0.2°, 21.1° ± 0.2°, 21.5° ± 0.2°, 23.2° ± 0.2°, 23.6° ± 0.2°, 24.3° ± 0.2°, and 29.5° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.8° ± 0.2°, 20.5° ± 0.2°, 21.1° ± 0.2°, 21.5° ± 0.2°, 23.2° ± 0.2°, 23.6° ± 0.2°, 24.3° ± 0.2°, and 29.5° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 20.5° ± 0.2°, 21.1° ± 0.2°, 21.5° ± 0.2°, 23.2° ± 0.2°, 23.6° ± 0.2°, 24.3° ± 0.2°, 29.5° ± 0.2°, and 29.8° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.8° ± 0.2°, 15.3° ± 0.2°, 20.5° ± 0.2°, 21.1° ± 0.2°, 21.5° ± 0.2°, 23.2° ± 0.2°, 23.6° ± 0.2°, 24.3° ± 0.2°, 29.5° ± 0.2°, and 29.8° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern substantially as shown in FIG. 13 , wherein by “substantially” is meant that the reported peaks can vary by about ± 0.2°2θ.

It is understood that peak intensities can vary from one diffractogram to another for the same crystalline form based on any number of factors that are known to those skilled in the art, such as, preferred orientation effects, preparation technique, the sample mounting procedure, the instrument employed, etc. In some instances, peak intensities can be rather dramatical. Accordingly, the diffraction peak intensities shown herein are illustrative and identical diffraction peak intensities are not necessarily required. One skilled in the art would readily be capable of comparing the diffractogram provided herein with a diffractogram generated for an unknown crystal form and confirm whether the diffractogram is characterizing the same crystal form as provided herein or a different form.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt), wherein the anhydrous crystalline form has a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an extrapolated onset temperature of about 154° C. to about 164° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 155° C. to about 163° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 157° C. to about 162° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 158.5° C. to about 160.5° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 159° C. to about 160° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram substantially as shown in FIG. 14 , wherein by “substantially” is meant that the reported DSC features can vary by about ± 5° C. and the reported DSC features can vary by about ± 20 joules per gram.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile showing about 1.0% or less weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.8% or less weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.6% or less weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.4% or less weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.35% or less weight loss out to about 125° C.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile showing about 0.05% to about 1.0% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.1% to about 0.8% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.15% to about 0.6% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.2% to about 0.4% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.25% to about 0.35% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile substantially as shown in FIG. 14 , wherein by “substantially” is meant that the reported TGA features can vary by about ± 5° C., and the reported TGA features can vary by about ± 2% weight change (i.e., ± about 2% weight change).

One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern comprising at least three peaks,     in terms of 2θ, selected from the group consisting of: 13.7° ± 0.2°,     14.8° ± 0.2°, 15.3° ± 0.2°, 20.5° ± 0.2°, 21.1° ± 0.2°, 21.5° ±     0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.6° ± 0.2°, 24.3° ± 0.2°, 29.5°     ± 0.2°, and 29.8° ± 0.2°; -   a differential scanning calorimetry thermogram comprising an     endotherm with an extrapolated onset temperature of about 154° C. to     about 164° C.; and/or -   a thermogravimetric analysis profile showing about 0.05% to about     1.0% weight loss out to about 125° C.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern comprising peaks, in terms of     2θ, at 20.5° ± 0.2°, 21.1° ± 0.2°, 24.3° ± 0.2°, and 29.5° ± 0.2°; -   a differential scanning calorimetry thermogram comprising an     endotherm with an extrapolated onset temperature of about 157° C. to     about 162° C.; and/or -   a thermogravimetric analysis profile showing about 1.0% or less     weight loss out to about 125° C.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern comprising peaks, in terms of     2θ, at 20.5° ± 0.2°, 21.1° ± 0.2°, 24.3° ± 0.2°, 29.5° ± 0.2°, 23.2°     ± 0.2°, 15.3° ± 0.2°, and 14.8° ± 0.2°; -   a differential scanning calorimetry thermogram comprising an     endotherm with an extrapolated onset temperature of about 159° C. to     about 160° C.; and/or -   a thermogravimetric analysis profile showing about 0.4% or less     weight loss out to about 125° C.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern substantially as shown in FIG.     13 ; -   a differential scanning calorimetry thermogram substantially as     shown in FIG. 14 ; and/or -   a thermogravimetric analysis profile substantially as shown in FIG.     14 .

In some embodiments, the anhydrous crystalline form of (S)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt) can be isolated as the crystalline form described herein, with a crystalline purity of at least about 75% by weight. In some embodiments, about 80% by weight. In some embodiments, about 85% by weight. In some embodiments, about 90% by weight. In some embodiments, about 95% by weight. In some embodiments, about 96% by weight. In some embodiments, about 97% by weight. In some embodiments, about 98% by weight. In some embodiments, about 99% by weight.

E. 2-Cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A, Crystalline Form)

One aspect of the present invention relates to a novel anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A) and processes related thereto.

A summary of representative physical properties for the crystalline form are provided in Table 11 and Table 12.

TABLE 11 Compound 3A (Anhydrous) PXRD FIG. 15 : Peaks at 7.4, 14.7, 22.0, and 29.5°2θ TGA FIG. 16 : Decrease in weight of about 0.2% out to about 70° C. DSC FIG. 16 : Endotherm extrapolated onset temperature: about 28° C.

Certain other XRPD peaks for the crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A) are shown in Table 12 below.

TABLE 12 2-Theta Height (cps) 2-Theta Height (cps) 2-Theta Height (cps) 7.4 1386059 22.9 5778 29.3 43357 7.5 604834 23.3 1923 29.5 222224 14.7 991447 24.1 4228 30.0 4106 14.8 388924 24.3 3477 30.5 1841 19.8 19675 25.0 2327 36.0 1032 20.2 7057 27.0 1819 36.9 16603 21.9 24114 27.9 11066 37.1 65489 22.0 176012 28.7 2144

One aspect of the present invention relates to a crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A). In some embodiments, the crystal form is an anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A). An anhydrous crystalline form refers to a crystalline form that contains 2% or less of water. In some embodiments, the anhydrous crystalline form contains 1% or less water. In some embodiments, the water content is determined by Karl Fischer (KF) analysis.

One aspect of the present invention relates to an anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least three peaks, in terms of 2θ, selected from the group consisting of: 7.4° ± 0.2°, 7.5° ± 0.2°, 14.7° ± 0.2°, 14.8° ± 0.2°, 22.0° ± 0.2°, 29.5°, and 37.1° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least four peaks, in terms of 2θ, selected from the group consisting of: 7.4° ± 0.2°, 7.5° ± 0.2°, 14.7° ± 0.2°, 14.8° ± 0.2°, 22.0° ± 0.2°, 29.5°, and 37.1° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least five peaks, in terms of 2θ, selected from the group consisting of: 7.4° ± 0.2°, 7.5° ± 0.2°, 14.7° ± 0.2°, 14.8° ± 0.2°, 22.0° ± 0.2°, 29.5°, and 37.1° ± 0.2°.

One aspect of the present invention relates to an anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 7.4° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 7.5° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 14.7° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 14.8° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 7.4° ± 0.2°, and 14.7° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 7.4° ± 0.2°, and 14.8° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 7.5° ± 0.2°, and 14.7° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 7.5° ± 0.2°, and 14.8° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 7.4° ± 0.2°, 14.7° ± 0.2°, and 22.0° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 7.4° ± 0.2°, 14.8° ± 0.2°, and 22.0° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 7.5° ± 0.2°, 14.7° ± 0.2°, and 22.0° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 7.5° ± 0.2°, 14.8° ± 0.2°, and 22.0° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 7.4° ± 0.2°, 14.7° ± 0.2°, and 29.5° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 7.4° ± 0.2°, 14.8° ± 0.2°, and 29.5° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20̸, at 7.5° ± 0.2°, 14.7° ± 0.2°, and 29.5° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 7.5° ± 0.2°, 14.8° ± 0.2°, and 29.5° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 7.4° ± 0.2°, 14.7° ± 0.2°, 22.0° ± 0.2°, and 29.5° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 7.4° ± 0.2°, 14.8° ± 0.2°, 22.0° ± 0.2°, and 29.5° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 7.5° ± 0.2°, 14.7° ± 0.2°, 22.0° ± 0.2°, and 29.5° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 7.5° ± 0.2°, 14.8° ± 0.2°, 22.0° ± 0.2°, and 29.5° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 7.4° ± 0.2°, 14.7° ± 0.2°, 22.0° ± 0.2°, 29.5° ± 0.2°, and 37.1° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 7.4° ± 0.2°, 14.8° ± 0.2°, 22.0° ± 0.2°, 29.5° ± 0.2°, and 37.1° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 7.5° ± 0.2°, 14.7° ± 0.2°, 22.0° ± 0.2°, 29.5° ± 0.2°, and 37.1° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 7.5° ± 0.2°, 14.8° ± 0.2°, 22.0° ± 0.2°, 29.5° ± 0.2°, and 37.1° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 7.4° ± 0.2°, 7.5° ± 0.2°, 14.7° ± 0.2°, 14.8° ± 0.2°, 22.0° ± 0.2°, 29.5° ± 0.2°, and 37.1° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern substantially as shown in FIG. 15 , wherein by “substantially” is meant that the reported peaks can vary by about ± 0.2 °2θ.

It is understood that peak intensities can vary from one diffractogram to another for the same crystalline form based on any number of factors that are known to those skilled in the art, such as, preferred orientation effects, preparation technique, the sample mounting procedure, the instrument employed, etc. In some instances, peak intensities can be rather dramatical. Accordingly, the diffraction peak intensities shown herein are illustrative and identical diffraction peak intensities are not necessarily required. One skilled in the art would readily be capable of comparing the diffractogram provided herein with a diffractogram generated for an unknown crystal form and confirm whether the diffractogram is characterizing the same crystal form as provided herein or a different form.

One aspect of the present invention relates to an anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A), wherein the anhydrous crystalline form has a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an extrapolated onset temperature of about 25° C. to about 31° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 26.5° C. to about 30° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 26.5° C. to about 29.5° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 27° C. to about 29° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 27.5° C. to about 28.5° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram substantially as shown in FIG. 16 , wherein by “substantially” is meant that the reported DSC features can vary by about ± 5° C. and the reported DSC features can vary by about ± 20 joules per gram.

One aspect of the present invention relates to an anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile showing about 1.0% or less weight loss out to about 70° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.7% or less weight loss out to about 70° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.6% or less weight loss out to about 70° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.4% or less weight loss out to about 70° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.2% or less weight loss out to about 70° C.

One aspect of the present invention relates to an anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile showing about 0.02% to about 1.0% weight loss out to about 70° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.03% to about 0.7% weight loss out to about 70° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.04% to about 0.6% weight loss out to about 70° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.05% to about 0.4% weight loss out to about 70° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.1% to about 0.2% weight loss out to about 70° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile substantially as shown in FIG. 16 , wherein by “substantially” is meant that the reported TGA features can vary by about ± 5° C., and the reported TGA features can vary by about ± 2% weight change (i.e., ± about 2% weight change).

One aspect of the present invention relates to an anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern comprising at least three peaks,     in terms of 2θ, selected from the group consisting of: 7.4° ± 0.2°,     7.5° ± 0.2°, 14.7° ± 0.2°, 14.8° ± 0.2°, 22.0° ± 0.2°, 29.5°, and     37.1° ± 0.2°; -   a differential scanning calorimetry (DSC) thermogram comprising an     endotherm with an extrapolated onset temperature of about 25° C. to     about 31° C.; and/or -   a thermogravimetric analysis profile showing about 1.0% or less     weight loss out to about 70° C.

One aspect of the present invention relates to an anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern comprising at least four peaks,     in terms of 2θ, selected from the group consisting of: 7.4° ± 0.2°,     7.5° ± 0.2°, 14.7° ± 0.2°, 14.8° ± 0.2°, 22.0° ± 0.2°, 29.5°, and     37.1° ± 0.2°; -   a differential scanning calorimetry thermogram comprising an     endotherm with an extrapolated onset temperature of about 26.5° C.     to about 29.5° C.; and/or -   a thermogravimetric analysis profile showing about 0.02% to about     1.0% weight loss out to about 70° C.

One aspect of the present invention relates to an anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern comprising peaks, in terms of     2θ, at 7.4° ± 0.2°, 7.5° ± 0.2°, 14.7° ± 0.2°, 14.8° ± 0.2°, 22.0° ±     0.2°, 29.5° ± 0.2°, and 37.1° ± 0.2°; -   a differential scanning calorimetry thermogram comprising an     endotherm with an extrapolated onset temperature of about 27.5° C.     to about 28.5° C.; and/or -   a thermogravimetric analysis profile showing about 0.05% to about     0.4% weight loss out to about 70° C.

One aspect of the present invention relates to an anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern substantially as shown in FIG.     15 ; -   a differential scanning calorimetry thermogram substantially as     shown in FIG. 16 ; and/or -   a thermogravimetric analysis profile substantially as shown in FIG.     16 .

In some embodiments, the anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A) can be isolated as the crystalline form described herein, with a crystalline purity of at least about 75% by weight. In some embodiments, about 80% by weight. In some embodiments, about 85% by weight. In some embodiments, about 90% by weight. In some embodiments, about 95% by weight. In some embodiments, about 96% by weight. In some embodiments, about 97% by weight. In some embodiments, about 98% by weight. In some embodiments, about 99% by weight.

F. Crystalline (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt)

One aspect of the present invention relates to a novel anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt) and processes related thereto.

A summary of representative physical properties for crystalline Compound 5A (HCl salt) are provided in Table 13 and Table 14.

TABLE 13 Compound 5A PXRD FIG. 17 : Peaks at 12.1, 13.0, 14.2, 19.5, 20.4, 25.9°2θ TGA FIG. 18 : Decrease in weight of about 0.1% out to about 125° C. DSC FIG. 18 : Endotherm extrapolated onset temperature: about 215.7° C.

Certain other XRPD peaks for the anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt) are shown in Table 14 below.

TABLE 14 2-Theta Height (cps) 2-Theta Height (cps) 2-Theta Height (cps) 5.6 635 23.5 5206 34.7 2218 6.5 4164 24.1 819 37.1 460 11.2 1737 24.5 4905 37.3 2290 11.6 840 24.8 6021 37.8 2072 12.1 14378 25.0 2188 38.1 5892 13.0 51387 25.9 33361 38.4 5410 14.2 10968 26.5 2447 38.6 3220 15.1 1951 26.9 2322 39.7 573 18.3 570 27.3 1464 40.4 2308 19.1 857 28.6 488 40.8 1119 19.5 28622 29.4 1081 41.9 765 20.1 10642 29.9 2004 42.4 404 20.4 16183 30.9 2169 42.9 549 21.0 1222 32.1 6743 43.6 450 21.9 8494 32.6 4016 44.0 1094 22.5 1443 33.2 1404 44.4 1022

One aspect of the present invention relates to a crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt). In some embodiments, the crystal form is an anhydrous crystalline form of (S)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)-N-((S)1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt). An anhydrous crystalline form refers to a crystalline form that contains 2% or less of water. In some embodiments, the anhydrous crystalline form contains 1% or less water. In some embodiments, the water content is determined by Karl Fischer (KF) analysis.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least three peaks, in terms of 2θ, selected from the group consisting of: 6.5° ± 0.2°, 12.1° ± 0.2°, 13.0° ± 0.2°, 14.2° ± 0.2°, 19.5° ± 0.2°, 20.1° ± 0.2°, 20.4° ± 0.2°, 21.9° ± 0.2°, 23.5° ± 0.2°, 24.5° ± 0.2°, 24.8° ± 0.2°, 25.9° ± 0.2°, and 32.1° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least four peaks, in terms of 2θ, selected from the group consisting of: 6.5° ± 0.2°, 12.1° ± 0.2°, 13.0° ± 0.2°, 14.2° ± 0.2°, 19.5° ± 0.2°, 20.1° ± 0.2°, 20.4° ± 0.2°, 21.9° ± 0.2°, 23.5° ± 0.2°, 24.5° ± 0.2°, 24.8° ± 0.2°, 25.9° ± 0.2°, and 32.1° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least five peaks, in terms of 2θ, selected from the group consisting of: 6.5° ± 0.2°, 12.1° ± 0.2°, 13.0° ± 0.2°, 14.2° ± 0.2°, 19.5° ± 0.2°, 20.1° ± 0.2°, 20.4° ± 0.2°, 21.9° ± 0.2°, 23.5° ± 0.2°, 24.5° ± 0.2°, 24.8° ± 0.2°, 25.9° ± 0.2°, and 32.1° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least six peaks, in terms of 2θ, selected from the group consisting of: 6.5° ± 0.2°, 12.1° ± 0.2°, 13.0° ± 0.2°, 14.2° ± 0.2°, 19.5° ± 0.2°, 20.1° ± 0.2°, 20.4° ± 0.2°, 21.9° ± 0.2°, 23.5° ± 0.2°, 24.5° ± 0.2°, 24.8° ± 0.2°, 25.9° ± 0.2°, and 32.1 ° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least seven peaks, in terms of 2θ, selected from the group consisting of: 6.5° ± 0.2°, 12.1° ± 0.2°, 13.0° ± 0.2°, 14.2° ± 0.2°, 19.5° ± 0.2°, 20.1° ± 0.2°, 20.4° ± 0.2°, 21.9° ± 0.2°, 23.5° ± 0.2°, 24.5° ± 0.2°, 24.8° ± 0.2°, 25.9° ± 0.2°, and 32.1° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least eight peaks, in terms of 2θ, selected from the group consisting of: 6.5° ± 0.2°, 12.1° ± 0.2°, 13.0° ± 0.2°, 14.2° ± 0.2°, 19.5° ± 0.2°, 20.1° ± 0.2°, 20.4° ± 0.2°, 21.9° ± 0.2°, 23.5° ± 0.2°, 24.5° ± 0.2°, 24.8° ± 0.2°, 25.9° ± 0.2°, and 32.1° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least nine peaks, in terms of 2θ, selected from the group consisting of: 6.5° ± 0.2°, 12.1° ± 0.2°, 13.0° ± 0.2°, 14.2° ± 0.2°, 19.5° ± 0.2°, 20.1° ± 0.2°, 20.4° ± 0.2°, 21.9° ± 0.2°, 23.5° ± 0.2°, 24.5° ± 0.2°, 24.8° ± 0.2°, 25.9° ± 0.2°, and 32.1° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least ten peaks, in terms of 2θ, selected from the group consisting of: 6.5° ± 0.2°, 12.1° ± 0.2°, 13.0° ± 0.2°, 14.2° ± 0.2°, 19.5° ± 0.2°, 20.1° ± 0.2°, 20.4° ± 0.2°, 21.9° ± 0.2°, 23.5° ± 0.2°, 24.5° ± 0.2°, 24.8° ± 0.2°, 25.9° ± 0.2°, and 32.1° ± 0.2°.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 13.0° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 19.5° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 25.9° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 13.0° ± 0.2° and 19.5° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 13.0° ± 0.2° and 25.9° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 19.5° ± 0.2° and 25.9° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 13.0° ± 0.2°, 19.5° ± 0.2°, and 25.9° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 13.0° ± 0.2°, 19.5° ± 0.2°, 20.4° ± 0.2°, and 25.9° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 12.1° ± 0.2°, 13.0° ± 0.2°, 19.5° ± 0.2°, 20.4° ± 0.2°, and 25.9° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 12.1° ± 0.2°, 13.0° ± 0.2°, 14.2° ± 0.2°, 19.5° ± 0.2°, 20.4° ± 0.2°, and 25.9° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 12.1° ± 0.2°, 13.0° ± 0.2°, 14.2° ± 0.2°, 19.5° ± 0.2°, 20.1° ± 0.2°, 20.4° ± 0.2°, 21.9° ± 0.2°, and 25.9° ± 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern substantially as shown in FIG. 17 , wherein by “substantially” is meant that the reported peaks can vary by about ± 0.2 °2θ.

It is understood that peak intensities can vary from one diffractogram to another for the same crystalline form based on any number of factors that are known to those skilled in the art, such as, preferred orientation effects, preparation technique, the sample mounting procedure, the instrument employed, etc. In some instances, peak intensities can be rather dramatical. Accordingly, the diffraction peak intensities shown herein are illustrative and identical diffraction peak intensities are not necessarily required. One skilled in the art would readily be capable of comparing the diffractogram provided herein with a diffractogram generated for an unknown crystal form and confirm whether the diffractogram is characterizing the same crystal form as provided herein or a different form.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N ((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt), wherein the anhydrous crystalline form has a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an extrapolated onset temperature of about 212° C. to about 218.5° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 213° C. to about 218° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 214° C. to about 217.5° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 214.5° C. to about 217° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 215° C. to about 216.5° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram substantially as shown in FIG. 18 , wherein by “substantially” is meant that the reported DSC features can vary by about ± 5° C. and the reported DSC features can vary by about ± 20 joules per gram.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N ((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile showing about 1.0% or less weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.8% or less weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.6% or less weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.4% or less weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.2% or less weight loss out to about 125° C.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N ((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile showing about 0.01% to about 1.0% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.02% to about 0.8% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.03% to about 0.6% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.04% to about 0.4% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.05% to about 0.2% weight loss out to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile substantially as shown in FIG. 18 , wherein by “substantially” is meant that the reported TGA features can vary by about ± 5° C., and the reported TGA features can vary by about ± 2% weight change (i.e., ± about 2% weight change).

One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N ((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern comprising at least three peaks,     in terms of 2θ, selected from the group consisting of: 6.5° ± 0.2°,     12.1° ± 0.2°, 13.0° ± 0.2°, 14.2° ± 0.2°, 19.5° ± 0.2°, 20.1° ±     0.2°, 20.4° ± 0.2°, 21.9° ± 0.2°, 23.5° ± 0.2°, 24.5° ± 0.2°, 24.8°     ± 0.2°, 25.9° ± 0.2°, and 32.1° ± 0.2°; -   a differential scanning calorimetry (DSC) thermogram comprising an     endotherm with an extrapolated onset temperature of about 212° C. to     about 218.5° C.; and/or -   a thermogravimetric analysis profile showing about 1.0% or less     weight loss out to about 125° C.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N ((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern comprising peaks, in terms of     2θ, selected from the group consisting of: 13.0° ± 0.2°, 19.5° ±     0.2°, and 25.9° ± 0.2°; -   a differential scanning calorimetry thermogram comprising an     endotherm with an extrapolated onset temperature of about 214° C. to     about 217.5° C.; and/or -   a thermogravimetric analysis profile showing about 0.02% to about     0.8% weight loss out to about 125° C.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N ((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern comprising peaks, in terms of     2θ, at 12.1° ± 0.2°, 13.0° ± 0.2°, 14.2° ± 0.2°, 19.5° ± 0.2°, 20.4°     ± 0.2°, and 25.9° ± 0.2°; -   a differential scanning calorimetry thermogram comprising an     endotherm with an extrapolated onset temperature of about 214.5° C.     to about 217° C.; and/or -   a thermogravimetric analysis profile showing about 0.04% to about     0.4% weight loss out to about 125° C.

One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N ((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern substantially as shown in FIG.     17 ; -   a differential scanning calorimetry thermogram substantially as     shown in FIG. 18 ; and/or -   a thermogravimetric analysis profile substantially as shown in FIG.     18 .

In some embodiments, the anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt) can be isolated as the crystalline form described herein, with a crystalline purity of at least about 75% by weight. In some embodiments, about 80% by weight. In some embodiments, about 85% by weight. In some embodiments, about 90% by weight. In some embodiments, about 95% by weight. In some embodiments, about 96% by weight. In some embodiments, about 97% by weight. In some embodiments, about 98% by weight. In some embodiments, about 99% by weight.

G. Crystalline 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, Tosylate Salt, Form I)

One aspect of the present invention relates to a novel crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt) and processes related thereto.

A summary of representative physical properties for crystalline Compound 1 (tosylate salt) are provided in Table 15 and Table 16.

TABLE 15 Crystalline Compound 1 (Tosylate salt, Form I) PXRD FIG. 24 : Peaks at 9.1, 10.5, 11.3, 20.4, 21.1, 22.8, 23.3, and 23.8°2θ TGA FIG. 25 : Decrease in weight of about 0.5% out to about 125° C. DSC FIG. 25 : Endotherm extrapolated onset temperature: about 155.7° C.

Certain other XRPD peaks for crystalline 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt) are shown in Table 16 below.

TABLE 16 Selected X-Ray Powder Diffraction (XRPD) Peaks for Compound 1 (tosylate salt, Form I) 2-Theta Height (cps) 2-Theta Height (cps) 2-Theta Height (cps) 8.1 957 20.7 3040 30.0 849 9.1 12296 21.1 11498 30.6 1262 9.5 4519 21.7 4979 30.8 1121 10.5 8507 21.9 5331 31.6 5563 11.3 10211 22.3 3701 32.7 874 13.2 6158 22.8 10159 33.7 1111 13.5 1598 23.3 14954 34.4 2054 14.2 2197 23.5 3597 34.8 706 15.2 1746 23.8 9590 35.1 1320 15.7 1437 24.7 2325 35.7 1028 16.3 5723 25.5 1704 38.4 751 16.7 3848 26.1 2413 39.7 1790 17.5 1578 26.7 422 40.2 762 19.0 6774 27.2 1648 41.2 925 19.3 6491 27.6 2825 43.2 1540 19.5 3152 28.5 6417 44.3 1142 20.4 8581 29.5 1423

One aspect of the present invention relates to an crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt, Form I).

One aspect of the present invention relates to an crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt, Form I), wherein the crystalline form has an X-ray powder diffraction pattern comprising at least three peaks, in terms of 2θ, selected from the group consisting of: 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 16.3° ± 0.2°, 19.0° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 22.8° ± 0.2°, 23.3° ± 0.2°, 23.8° ± 0.2°, and 28.5° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising at least four peaks, in terms of 2θ, selected from the group consisting of: 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 16.3° ± 0.2°, 19.0° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 22.8° ± 0.2°, 23.3° ± 0.2°, 23.8° ± 0.2°, and 28.5° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising at least five peaks, in terms of 2θ, selected from the group consisting of: 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 16.3° ± 0.2°, 19.0° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 22.8° ± 0.2°, 23.3° ± 0.2°, 23.8° ± 0.2°, and 28.5° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising at least six peaks, in terms of 2θ, selected from the group consisting of: 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 16.3° ± 0.2°, 19.0° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 22.8° ± 0.2°, 23.3° ± 0.2°, 23.8° ± 0.2°, and 28.5° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising at least seven peaks, in terms of 2θ, selected from the group consisting of: 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 16.3° ± 0.2°, 19.0° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 22.8° ± 0.2°, 23.3° ± 0.2°, 23.8° ± 0.2°, and 28.5° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising at least eight peaks, in terms of 2θ, selected from the group consisting of: 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 16.3° ± 0.2°, 19.0° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 22.8° ± 0.2°, 23.3° ± 0.2°, 23.8° ± 0.2°, and 28.5° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising at least nine peaks, in terms of 2θ, selected from the group consisting of: 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 16.3° ± 0.2°, 19.0° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 22.8° ± 0.2°, 23.3° ± 0.2°, 23.8° ± 0.2°, and 28.5° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising at least ten peaks, in terms of 2θ, selected from the group consisting of: 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 16.3° ± 0.2°, 19.0° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 22.8° ± 0.2°, 23.3° ± 0.2°, 23.8° ± 0.2°, and 28.5° ± 0.2°.

One aspect of the present invention relates to a crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt), wherein the crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 9.1° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 21.1° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 23.3° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2° and 21.1° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2° and 23.3° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 21.1° ± 0.2° and 23.3° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 21.1° ± 0.2°, and 23.3° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 11.3° ± 0.2°, 21.1° ± 0.2°, and 23.3° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 11.3° ± 0.2°, 21.1° ± 0.2°, 22.8° ± 0.2°, and 23.3° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 16.3° ± 0.2°, and 21.1° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 9.1° ± 0.2°, 11.3° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 11.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 19.0° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, 23.8° ± 0.2°, and 28.5° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 19.0° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, 23.8° ± 0.2°, and 28.5° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 16.3° ± 0.2°, 19.0° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 16.3° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 16.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, 23.8° ± 0.2°, and 28.5° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 19.0° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, 23.8° ± 0.2°, and 28.5° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 16.3° ± 0.2°, 19.0° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, 23.8° ± 0.2°, and 28.5° ± 0.2°. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern substantially as shown in FIG. 24 , wherein by “substantially” is meant that the reported peaks can vary by about ± 0.2°2θ.

It is understood that peak intensities can vary from one diffractogram to another for the same crystalline form based on any number of factors that are known to those skilled in the art, such as, preferred orientation effects, preparation technique, the sample mounting procedure, the instrument employed, etc. In some instances, peak intensities can be rather dramatical. Accordingly, the diffraction peak intensities shown herein are illustrative and identical diffraction peak intensities are not necessarily required. One skilled in the art would readily be capable of comparing the diffractogram provided herein with a diffractogram generated for an unknown crystal form and confirm whether the diffractogram is characterizing the same crystal form as provided herein or a different form.

One aspect of the present invention relates to a crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt), wherein the crystalline form has a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an extrapolated onset temperature of about 154° C. to about 159° C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 154.5° C. to about 158.5° C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 155° C. to about 158° C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 155.5° C. to about 157.5° C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 156° C. to about 157° C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a differential scanning calorimetry thermogram substantially as shown in FIG. 25 , wherein by “substantially” is meant that the reported DSC features can vary by about ±5° C. and the reported DSC features can vary by about ± 20 joules per gram.

One aspect of the present invention relates to a crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt), wherein the crystalline form has a thermogravimetric analysis (TGA) profile showing about 1.0% or less weight loss out to about 125° C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a thermogravimetric analysis (TGA) profile showing about 0.9% or less weight loss out to about 125° C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a thermogravimetric analysis (TGA) profile showing about 0.7% or less weight loss out to about 125° C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a thermogravimetric analysis (TGA) profile showing about 0.6% or less weight loss out to about 125° C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a thermogravimetric analysis (TGA) profile showing about 0.5% or less weight loss out to about 125° C.

One aspect of the present invention relates to a crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt), wherein the crystalline form has a thermogravimetric analysis (TGA) profile showing about 0.05% to about 1.0% weight loss out to about 125° C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a thermogravimetric analysis (TGA) profile showing about 0.1% to about 0.9% weight loss out to about 125° C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a thermogravimetric analysis (TGA) profile showing about 0.2% to about 0.7% weight loss out to about 125° C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a thermogravimetric analysis (TGA) profile showing about 0.3% to about 0.6% weight loss out to about 125° C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a thermogravimetric analysis (TGA) profile showing about 0.4% to about 0.5% weight loss out to about 125° C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a thermogravimetric analysis profile substantially as shown in FIG. 25 , wherein by “substantially” is meant that the reported TGA features can vary by about ± 5° C., and the reported TGA features can vary by about ± 2% weight change (i.e., ± about 2% weight change).

One aspect of the present invention relates to an crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt), wherein the crystalline form has:

-   an X-ray powder diffraction pattern comprising at least three peaks,     in terms of 2θ, selected from the group consisting of: 9.1° ± 0.2°,     10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 16.3° ± 0.2°, 19.0° ±     0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 22.8° ± 0.2°, 23.3°     ± 0.2°, 23.8° ± 0.2°, and 28.5° ± 0.2°; -   a differential scanning calorimetry thermogram comprising an     endotherm with an extrapolated onset temperature of about 154° C. to     about 159° C.; and/or -   a thermogravimetric analysis profile showing about 0.05% to about     1.0% weight loss out to about 125° C.

One aspect of the present invention relates to an crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern comprising peaks, in terms of     2θ, at 9.1° ± 0.2°, 11.3° ± 0.2°, 21.1° ± 0.2°, 22.8° ± 0.2°, and     23.3° ± 0.2°; -   a differential scanning calorimetry thermogram comprising an     endotherm with an extrapolated onset temperature of about 155° C. to     about 158° C.; and/or -   a thermogravimetric analysis profile showing about 0.9% or less     weight loss out to about 125° C.

One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern comprising peaks, in terms of     2θ, at 9.1° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 16.3° ± 0.2°, and     21.1° ± 0.2°; -   a differential scanning calorimetry thermogram comprising an     endotherm with an extrapolated onset temperature of about 155.5° C.     to about 157.5° C.; and/or -   a thermogravimetric analysis profile showing about 0.6% or less     weight loss out to about 125° C.

One aspect of the present invention relates to a crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt), wherein the anhydrous crystalline form has:

-   an X-ray powder diffraction pattern substantially as shown in FIG.     24 ; -   a differential scanning calorimetry thermogram substantially as     shown in FIG. 25 ; and/or -   a thermogravimetric analysis profile substantially as shown in FIG.     25 .

In some embodiments, the anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt) can be isolated as the crystalline form described herein, with a crystalline purity of at least about 75% by weight. In some embodiments, about 80% by weight. In some embodiments, about 85% by weight. In some embodiments, about 90% by weight. In some embodiments, about 95% by weight. In some embodiments, about 96% by weight. In some embodiments, about 97% by weight. In some embodiments, about 98% by weight. In some embodiments, about 99% by weight.

Isotopically Labeled Compounds of the Invention

The compounds disclosed and described herein allow atoms at each position of the compound independently to have an isotopic distribution for a chemical element in proportional amounts to those usually found in nature or an isotopic distribution in proportional amounts different to those usually found in nature unless the context clearly dictates otherwise. Accordingly, one aspect of the present invention relates to Compounds of Formula (Ia):

wherein:

-   R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are each     independently selected from the group consisting of hydrogen and     deuterium; and -   X is selected from the group consisting of carbon-12 (¹²C) and     carbon-13 (¹³C); provided that at least one R¹, R², R³, R⁴, R⁵, R⁶,     R⁷, R⁸, R⁹, R¹⁰, and R¹¹ is deuterium.

In some embodiments, each R¹ is independently deuterium. In some embodiments, each R² is independently deuterium. In some embodiments, each R³ is independently deuterium. In some embodiments, R⁴ is deuterium. In some embodiments, each R⁵ is independently deuterium. In some embodiments, each R⁶ is independently deuterium. In some embodiments, each R⁷ is independently deuterium. In some embodiments, each R⁸ is independently deuterium. In some embodiments, each R⁹ is independently deuterium. In some embodiments, R¹⁰ is deuterium. In some embodiments, R¹¹is deuterium.

In some embodiments, X is carbon-12 (¹²C). In some embodiments, X is carbon-13 (¹³C).

In some embodiments, each R¹ is independently deuterium and X is carbon-13 (¹³C).

Compounds of Formula (Ia) can be prepared using processes described herein by introducing one or more isotopes into any of the intermediates using methods known in the art, such as, the representative process shown in Example 6.

A chemical element has an atomic number defined by the number of protons within the atom’s nucleus. Each atomic number identifies a specific element, but not the isotope; an atom of a given element can have a wide range in its number of neutrons. The number of both protons and neutrons in the nucleus is the atom’s mass number, and each isotope of a given element has a different mass number. A compound wherein one or more atoms have an isotopic distribution for a chemical element in proportional amounts different to those usually found in nature is commonly referred to as being an isotopically labeled compound. Each chemical element as represented in a compound structure can include any isotopic distribution of said element. For example, in a compound structure a hydrogen atom can be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom can be present, the hydrogen atom can be an isotopic distribution of hydrogen, including but not limited to protium (¹H) and deuterium (²H) in proportional amounts to those usually found in nature and in proportional amounts different to those usually found in nature. Thus, reference herein to a compound encompasses all potential isotopic distributions for each atom unless the context clearly dictates otherwise. Examples of isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, bromine and iodine. As one of skill in the art would appreciate, any of the compounds as disclosed and described herein can include radioactive isotopes. Accordingly, also contemplated is use of compounds as disclosed and described herein, wherein one or more atoms have an isotopic distribution different to those usually found in nature, such as having ²H or ³H in greater proportion, or ¹¹C, ¹³C, or ¹⁴C in greater proportion than found in nature. By way of general example, and without limitation, isotopes of hydrogen include protium (¹H), deuterium (²H) and tritium (³H). Isotopes of carbon include carbon-11 (¹¹C), carbon-12 (¹²C), carbon-13 (¹³C), and carbon-14 (¹⁴C). Isotopes of nitrogen include nitrogen-13 (¹³N), nitrogen-14 (¹⁴N) and nitrogen-15 (¹⁵N). Isotopes of oxygen include oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), oxygen-16 (¹⁶O), oxygen-17 (¹⁷O), and oxygen-18 (¹⁸O). Isotope of fluorine include fluorine-17 (¹⁷F), fluorine-18 (¹⁸F) and fluorine-19 (¹⁹F). Isotopes of phosphorous include phosphorus-31 (³¹P), phosphorus-32 (³²P), phosphorus-33 (³³P), phosphorus-34 (³⁴P), phosphorus-35 (³⁵P) and phosphorus-36 (³⁶P). Isotopes of sulfur include sulfur-32 (³²S), sulfur-33 (³³S), sulfur-34 (³⁴S), sulfur-35 (³⁵S), sulfur-36 (³⁶S) and sulfur-38 (³⁸S). Isotopes of chlorine include chlorine-35 (³⁵C1), chlorine-36 (³⁶C1) and chlorine-37 (³⁷C1). Isotopes of bromine include bromine-75 (⁷⁵Br), bromine-76 (⁷⁶Br), bromine-77 (⁷⁷Br), bromine-79 (⁷⁹Br), bromine-81 (⁸¹Br) and bromine-82 (⁸²Br). Isotopes of iodine include iodine-123 (¹²³I), iodine-124 (¹²⁴I), iodine-125 (¹²⁵I), iodine-131 (¹³¹I) and iodine-135 (¹³⁵I). In some embodiments, atoms at every position of the compound have an isotopic distribution for each chemical element in proportional amounts to those usually found in nature. In some embodiments, atoms at least one position of the compound has an isotopic distribution for a chemical element in proportional amounts different to those usually found in nature (remainder atoms having an isotopic distribution for a chemical element in proportional amounts to those usually found in nature). In some embodiments, atoms at least two positions of the compound independently have an isotopic distribution for a chemical element in proportional amounts different to those usually found in nature (remainder atoms having an isotopic distribution for a chemical element in proportional amounts to those usually found in nature). In some embodiments, atoms at least three positions of the compound independently have an isotopic distribution for a chemical element in proportional amounts different to those usually found in nature (remainder atoms having an isotopic distribution for a chemical element in proportional amounts to those usually found in nature). In some embodiments, atoms at least four positions of the compound independently have an isotopic distribution for a chemical element in proportional amounts different to those usually found in nature (remainder atoms having an isotopic distribution for a chemical element in proportional amounts to those usually found in nature). In some embodiments, atoms at least five positions of the compound independently have an isotopic distribution for a chemical element in proportional amounts different to those usually found in nature (remainder atoms having an isotopic distribution for a chemical element in proportional amounts to those usually found in nature). In some embodiments, atoms at least six positions of the compound independently have an isotopic distribution for a chemical element in proportional amounts different to those usually found in nature (remainder atoms having an isotopic distribution for a chemical element in proportional amounts to those usually found in nature).

With regard to the compounds provided herein, when a particular atomic position is designated as having deuterium or “D” or “d”, it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%. A position designated as having deuterium typically has a minimum isotopic enrichment factor of, in certain embodiments, at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium position.

Certain Processes of the Invention

The present invention is directed, inter alia, to processes useful in the preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N [(1S)-2-cyclopropyl-1-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) and crystalline forms thereof.

Any of the processes either, collectively as one or more steps together, or individual steps as described herein, infra and supra, can be conducted under an inert atmosphere. Accordingly, in some embodiments, the process step as described herein is conducted under a substantially inert atmosphere.

In some embodiments, the process step as described herein is conducted under a substantially inert atmosphere comprising argon or nitrogen. In some embodiments, the process step as described herein is conducted under a substantially inert atmosphere comprising nitrogen.

The reactions of the processes described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent’s freezing temperature to the solvent’s boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the reaction step, suitable solvents for a particular reaction step can be selected. In some embodiments, reactions can be carried out in the absence of solvent, such as when at least one of the intermediates or reagents is a liquid.

Suitable solvents can include halogenated solvents such as: carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane, 1,2-dichloroethane, 2-chloropropane, hexafluorobenzene, 1,2,4-trichlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, chlorobenzene, fluorobenzene, fluorotrichloromethane, chlorotrifluoromethane, bromotrifluoromethane, carbon tetrafluoride, dichlorofluoromethane, chlorodifluoromethane, trifluoromethane, 1,2-dichlorotetrafluorethane, hexafluoroethane, and mixtures thereof.

Suitable solvents can include ether solvents, such as: 1,2-dimethoxyethane (DME), tetrahydrofuran (THF), cyclopentyl methyl ether (CPME), 2-methyltetrahydrofuran (2-MeTHF), 1,3-dioxane, 1,4-dioxane, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, 5-methyl-2-hexanone (MIAK), 4-methyl-2-pentanone (MIBK), tert-amyl methyl ether (TAME, also referred to as 2-methoxy-2-methylbutane), methyl tert-butyl ether (MTBE), mixtures thereof.

Suitable solvents can include alcohol or protic solvents, such as: methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, isobutyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, glycerol, and mixtures thereof.

Suitable solvents can include aprotic solvents, such as: benzene, chlorobenzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptanes, n-heptane, ethylbenzene, o-xylene, m-xylene, p-xylene, mixtures of xylenes, octane, indane, nonane, naphthalene, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, isopropyl acetate, sulfolane, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidinone, tetramethylurea, nitromethane, and nitrobenzene, and amides, including but not limited to, N,Ndimethylformamide, N,Ndimethylacetamide, formamide, N-methylacetamide, N-methylformamide, N,N-dimethylpropionamide, hexamethylphosphoramide, and mixtures thereof.

Suitable hydrocarbon solvents include benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, naphthalene, and mixtures thereof.

The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or ¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, gas chromatography (GC), or by chromatography, such as, high performance liquid chromatography (HPLC) or thin layer chromatography.

Upon carrying out preparation of compounds according to the processes described herein, the usual isolation and purification operations such as concentration, filtration, extraction, solid-phase extraction, recrystallization, enantiomeric-enrichment via recrystallization, chromatography, and the like, may be used to isolate the desired product.

Example processes and certain intermediates of the present invention are shown in Scheme I to Scheme VII below.

A representative Coupling-Step of 2-cyclopropylacetic acid (Compound 1A) with N,O-dimethylhydroxylamine or a salt thereof in the presence of a coupling-step reagent (e.g., 1,1′-carbonyldiimidazole), a coupling-step base (e.g., triethylamine), and a coupling-step solvent (e.g., dichloromethane) to prepare 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A) is provided below in Scheme I.

A representative Reacting-Step between 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A) with an organomagnesium reagent of 4-bromo-2-fluoro-1-methylbenzene in the presence of a reacting-step solvent (e.g., tetrahydrofuran (THF)) to prepare 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A) is provided below in Scheme II.

A representative Condensing-Step of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A) with a Compound of Formula (Ic) or a salt thereof, in the presence of a condensing-step acid (e.g., p-toluenesulfonic acid) and a condensing-step solvent (e.g., toluene) to prepare a Compound of Formula (Ie) is provided below in Scheme III.

wherein:

-   R^(1c), R^(2c), and R^(3c) are each independently selected from: H,     C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen.

A representative Reducing-Step of a Compound of Formula (Ie) in the presence of a reducing-catalyst (e.g., sponge nickel and Pd/Cu-C), hydrogen, and a reducing-step solvent (e.g., ethanol) to prepare a Compound of Formula (Ig) is provided below in Scheme IV.

wherein:

-   R^(1c), R^(2c), and R^(3c) are each independently selected from: H,     C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen.

A representative Deprotecting-Step of a Compound of Formula (Ig), or a salt thereof, in the presence of a deprotecting-catalyst t (e.g., Pd), hydrogen, and a deprotecting-step solvent (e.g., ethanol) to prepare (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof is provided below in Scheme V.

wherein:

-   R^(1c), R^(2c), and R^(3c) are each independently selected from: H,     C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen.

A representative Cyclizing-Step of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof, with 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A) or a tautomeric form thereof, in the presence of a cyclizing-step solvent (e.g., n-heptane) to prepare (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof is provided below in Scheme VI.

A representative Alkylating-Step of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof, with a Compound of Formula (Ii), wherein LG is suitable leaving group (e.g., Br), in the presence of an alkylating-step solvent (e.g., methyl tert-butyl ether (MTBE), toluene, and mixtures thereof), a phase-transfer catalyst (e.g., tetra-n-butylammonium bromide (TBAB)), an alkylating-step base (e.g., potassium hydroxide), and water to prepare 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof is provided below in Scheme VII.

One aspect of the present invention includes every combination of one or more process steps and intermediates related thereto used in the preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), and/or pharmaceutically acceptable salts, and crystalline forms thereof, such as those processes exemplified by Schemes I, II, III, IV, V, VI, VII, and VII (supra) and Compounds contained therein.

One aspect of the present invention pertains to one or more of the intermediates, such as, Compounds (2A), (3A), (4A), (5A), (6A), (7A), (8A), and (9A); and compounds of Formulae (Ia), (Ic), (Ie), (Ig), and (Ii), and those compounds prepared by the processes exemplified in Schemes I, II, III, IV, V, VI, VII, and VII (supra), that are useful in the preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), and/or pharmaceutically acceptable salts, and crystalline forms thereof.

Certain synthetic processes for the preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) have been described in PCT application PCT/FR00/01995, filed 11 Jul. 2000 (International Publication Number WO2001/05776). Several improvements have been discovered and are described herein.

One such improvement is the use of PTC conditions as shown in Scheme VII which eliminated the need for moisture sensitive bases, such as sodium hydride, and dimethylformamide as described in WO2001/05776 (see Example 25).

Other improvements include the steps as shown in Scheme III to IV which converted ketone (Compound 3A) to the chiral amine (Compound 6A) in high yield and high enantiomeric excess.

Compounds of the invention also include all isotopes of atoms occurring in the intermediates and/or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers, for example, isotopes of hydrogen include deuterium and tritium.

I. Processes Useful for the Preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) or a pharmaceutical salt thereof (Alkylating-Step)

One aspect of the present invention relates to processes for preparing 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof:

comprising:

-   alkylating     (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine     (Compound 9A) or a salt thereof:

-   

-   with a Compound of Formula (Ii):

-   

-   wherein: LG is a leaving group;

-   in the presence of an alkylating-step solvent, a phase-transfer     catalyst, an alkylating-step base, and water to form     4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine     (Compound 1) or a pharmaceutically acceptable salt thereof.

In some embodiments, LG is selected from the group: C₁-C₄ alkylsulphonyloxy, C₆-C₁₀ arylsulfonyloxy, halogen, and hydroxy; wherein C₁-C₄ alkylsulphonyloxy and C₆-C₁₀ arylsulfonyloxy are each optionally substituted with one or more groups selected from the group: C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and nitro.

In some embodiments, the Compound of Formula (Ii) is a compound of the following Formula:

wherein the alkyl group is optionally substituted with one or more groups selected from the group: C₁-C₄ alkoxy, halogen, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and nitro. In some embodiments, the phrase “one or more groups” is one, two, or three groups. In some embodiments, the alkyl group is optionally substituted with one or more halogen groups. In some embodiments, the alkyl group is optionally substituted with one or more fluoro groups.

In some embodiments, the Compound of Formula (Ii) is a compound of the following Formula:

wherein: R^(1a), R^(2a), and R^(3a) are each selected independently from the group consisting of: H, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and nitro. In some embodiments, R^(1a), R^(2a), and R^(3a) are each selected independently from the group consisting of: H, methyl, methoxy, fluoro, chloro, bromo, iodo, trifluoromethyl, trifluoromethoxy, and nitro. In some embodiments, R^(1a), R^(2a), and R^(3a) are each selected independently from the group consisting of: H, methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, and nitro. In some embodiments, R^(1a), R^(2a), and R^(3a) are each selected independently from the group consisting of: H, methyl, fluoro, trifluoromethyl, trifluoromethoxy, and nitro. In some embodiments, R^(1a), R^(2a), and R^(3a) are each selected independently from the group consisting of: H and methyl.

In some embodiments, LG is halogen.

In some embodiments, LG is Cl, Br, or I.

In some embodiments, LG is Br.

In some embodiments, the Compound of Formula (Ii) is selected from the group consisting of: propargyl bromide, propargyl chloride, propargyl alcohol, propargyl methanesulfonate, propargyl trifluoromethanesulfonate, propargyl benzenesulfonate, and propargylp-toluenesulfonate. In some embodiments, the Compound of Formula (Ii) is selected from the group consisting of: propargyl bromide, propargyl methanesulfonate, propargyl trifluoromethanesulfonate, propargyl benzenesulfonate, and propargyl p-toluenesulfonate.

In some embodiments, the Compound of Formula (Ii) is propargyl bromide.

In some embodiments, the Compound of Formula (Ii) and Compound 9A are present in substantially equal molar quantities. In some embodiments, the Compound of Formula (Ii) is present in a molar excess compared to Compound 9A. In some embodiments, the Compound of Formula (Ii) is present in about 30% molar excess compared to Compound 9A. In some embodiments, the Compound of Formula (Ii) is present in about 25% molar excess compared to Compound 9A. In some embodiments, the Compound of Formula (Ii) is present in about 20% molar excess compared to Compound 9A.

In some embodiments, Compound 9A and the phase-transfer catalyst are present in substantially equal molar quantities. In some embodiments, the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.05 to about 1:0.9. In some embodiments, the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.05 to about 1:0.8. In some embodiments, the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.05 to about 1:0.7. In some embodiments, the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.05 to about 1:0.6. In some embodiments, the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.05 to about 1:0.5.

In some embodiments, the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.05 to about 1:0.4. In some embodiments, the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.1 to about 1.3:0.2. In some embodiments, the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.15.

In some embodiments, the molar ratio between Compound 9A, the phase-transfer catalyst, and the alkylating-step base is about 1:0.05:5 to about 1:0.4:25. In some embodiments, the molar ratio between Compound 9A, the phase-transfer catalyst, and the alkylating-step base is about 1:0.1:10 to about 1:0.2:20. In some embodiments, the molar ratio between Compound 9A, the phase-transfer catalyst, and the alkylating-step base is about 1:0.15:16.

In some embodiments, the alkylating-step solvent is any suitable solvent, such as, a solvent as described herein, or mixtures thereof.

In some embodiments, the alkylating-step solvent is selected from a halogenated solvent, an ether solvent, an aprotic solvent, and mixtures thereof. In some embodiments, the alkylating-step solvent is selected from: dichloromethane, tetrachloroethylene, 1,1-dichloroethane, 1,2-dichloroethane, 1,2-dichlorobenzene, chlorobenzene, 1,2-dimethoxyethane (DME), cyclopentyl methyl ether (CPME), 2-methyltetrahydrofuran (2-MeTHF), 1,4-dioxane, ethylene glycol diethyl ether, tert-amyl methyl ether (TAME, also referred to as 2-methoxy-2-methylbutane), methyl tert-butyl ether (MTBE), benzene, cyclohexane, hexane, toluene, cycloheptane, methylcyclohexane, heptanes, n-heptane, ethylbenzene, o-xylene, m-xylene, p-xylene, mixtures of xylenes, octane, and mixtures thereof. In some embodiments, the alkylating-step solvent is selected from: 1,2-dimethoxyethane (DME), cyclopentyl methyl ether (CPME), 2-methyltetrahydrofuran (2-MeTHF), 1,4-dioxane, ethylene glycol diethyl ether, tert-amyl methyl ether (TAME, also referred to as 2-methoxy-2-methylbutane), methyl tert-butyl ether (MTBE), benzene, toluene, and mixtures thereof. In some embodiments, the alkylating-step solvent is selected from: methyl tert-butyl ether (MTBE), toluene, and mixtures thereof.

In some embodiments, the phase-transfer catalyst is a quaternary ammonium salt. In some embodiments, the phase-transfer catalyst is a quaternary ammonium salt selected from: tricaprylyl methyl ammonium chloride (Aliquat 336), tetra-n-butylammonium bromide (TBAB), benzyltriethylammonium chloride (BTEAC), cetyltrimethylammonium bromide (CTAB), tetra-n-butylammonium chloride (TBAC), tetra-n-butylammonium hydroxide, tetra-n-butylammonium iodide, tetraethylammonium chloride (TEAC), benzyltributylammonium chloride (BTBAC), cetyltrimethylammonium chloride (CTAC), tetramethylammonium chloride, cetyltrimethylammonium chloride (CTAC), octyltrimethylammonium chloride, and combinations thereof. In some embodiments, the phase-transfer catalyst is tetra-n-butylammonium bromide (TBAB).

In some embodiments, the alkylating-step base is any suitable base, such as, a base as described herein, or mixtures thereof.

In some embodiments, the alkylating-step base an “inorganic base” as described herein.

In some embodiments, the alkylating-step base is an alkali metal hydroxide. In some embodiments, the alkylating-step base is an alkali metal hydroxide selected from: lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide. In some embodiments, the alkylating-step base is an alkali metal hydroxide selected from: sodium hydroxide and potassium hydroxide. In some embodiments, the alkylating-step base is potassium hydroxide.

In some embodiments, the alkylating step further comprises the steps of:

-   forming a first-alkylating mixture comprising the alkylating-step     solvent, the alkylating-catalyst, and Compound 9A at a     first-alkylating temperature; and -   adding the alkylating-step base and the Compound of Formula (Ii) to     the first-alkylating mixture at the first-alkylating temperature to     form an alkylating-biphasic mixture at a second-alkylating     temperature.

In some embodiments, the alkylating step further comprises heating the first-alkylating mixture comprising the alkylating-step solvent, the alkylating-catalyst, and Compound 9A to a temperature of about 40° C. to about 75° C. and subsequently cooling to the first-alkylating temperature. In some embodiments, the alkylating step further comprises heating first-alkylating mixture comprising the alkylating-step solvent, the alkylating-catalyst, and Compound 9A to a temperature of about 55° C. to about 65° C. and subsequently cooling to the first-alkylating temperature. In some embodiments, the alkylating step further comprises heating first-alkylating mixture comprising the alkylating-step solvent, the alkylating-catalyst, and Compound 9A to a temperature of about 60° C. and subsequently cooling to the first-alkylating temperature.

In some embodiments, adding the alkylating-step base to the first-alkylating mixture is conducted as a solution of the alkylating-step base in water.

In some embodiments, adding the alkylating-step base to the first-alkylating mixture is conducted as a solution of the alkylating-step base in water and the concentration in terms of percent weight/weight (% w/w) of the alkylating-step base and water is about 40 to about 60. In some embodiments, adding the alkylating-step base to the first-alkylating mixture is conducted as a solution of the alkylating-step base in water and the concentration in terms of percent weight/weight (% w/w) of the alkylating-step base and water is about 45 to about 55. In some embodiments, adding the alkylating-step base to the first-alkylating mixture is conducted as a solution of the alkylating-step base in water and the concentration in terms of percent weight/weight (% w/w) of the alkylating-step base and water is about 52 to about 53. In some embodiments, adding the alkylating-step base to the first-alkylating mixture is conducted as a solution of the alkylating-step base in water and the concentration in terms of percent weight/weight (% w/w) of the alkylating-step base and water is about 52.4.

In some embodiments, adding the Compound of Formula (Ii) to the first-alkylating mixture is conducted as a solution of the Compound of Formula (Ii) in the alkylating-step solvent. In some embodiments, adding the Compound of Formula (Ii) to the first-alkylating mixture is conducted as a solution of the Compound of Formula (Ii) in the alkylating-step solvent and the concentration in terms of percent weight/weight (% w/w) of the Compound of Formula (Ii) in the alkylating-step solvent is about 65 to about 90. In some embodiments, adding the Compound of Formula (Ii) to the first-alkylating mixture is conducted as a solution of the Compound of Formula (Ii) in the alkylating-step solvent and the concentration in terms of percent weight/weight (% w/w) of the Compound of Formula (Ii) in the alkylating-step solvent is about 75 to about 85. In some embodiments, adding the Compound of Formula (Ii) to the first-alkylating mixture is conducted as a solution of the Compound of Formula (Ii) in the alkylating-step solvent and the concentration in terms of percent weight/weight (% w/w) of the Compound of Formula (Ii) in the alkylating-step solvent is about 80.

In some embodiments, adding the alkylating-step base and the Compound of Formula (Ii) to the first-alkylating mixture is conducted concurrently at a rate to maintain the first-alkylating temperature.

In some embodiments, adding the alkylating-step base and the Compound of Formula (Ii) to the first-alkylating mixture is conducted serially at a rate to maintain the first-alkylating temperature. In some embodiments, serially is conducted by adding the alkylating-step base followed by adding the Compound of Formula (Ii) to the first-alkylating mixture at a rate to maintain the first-alkylating temperature during each addition.

In some embodiments, the first-alkylating temperature is about -15° C. to about 15° C. In some embodiments, the first-alkylating temperature is about -10° C. to about 10° C. In some embodiments, the first-alkylating temperature is about -5° C. to about 7° C. In some embodiments, the first-alkylating temperature is about 0° C. to about 5° C.

In some embodiments, the second-alkylating temperature is about -10° C. to about 20° C. In some embodiments, the second-alkylating temperature is about -5° C. to about 15° C. In some embodiments, the second-alkylating temperature is about 0° C. to about 10° C. In some embodiments, the second-alkylating temperature is about 4° C. to about 6° C.

In some embodiments, alkylating is conducted with stirring. In some embodiments, alkylating is conducted with vigorous stirring. In some embodiments, alkylating is conducted with vigorous stirring at a rate to increase the water and organic interface.

In some embodiments, the alkylating step further comprises preparing (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof, by the step of:

-   cyclizing (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine     (Compound 6A) or a salt thereof:

-   

-   with 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one     (Compound 8A) or a tautomeric form thereof:

-   

-   in the presence of a cyclizing-step solvent to form     (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine     (Compound 9A) or a salt thereof.

In some embodiments, the alkylating step further comprises preparing (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof, by the step of:

-   deprotecting a Compound of Formula (Ig), or a salt thereof,

-   

wherein:

-   R^(1c), R^(2c), and R^(3c) are each independently selected from: H,     C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen; -   in the presence of a deprotecting-catalyst, hydrogen, and a     deprotecting-step solvent to form     (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound     6A) or a salt thereof.

In some embodiments, the alkylating step further comprises preparing a Compound of Formula (Ig), or a salt thereof,

wherein:

-   R^(1c), R^(2c), and R^(3c) are each independently selected from: H,     C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen;

-   comprising:

-   reducing a Compound of Formula (Ie):

-   

wherein:

-   R^(1c), R^(2c), and R^(3c) are each independently selected from: H,     C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen; -   in the presence of a reducing-catalyst, hydrogen, and a     reducing-step solvent to form the Compound of Formula (Ig), or a     salt thereof.

In some embodiments, the alkylating step further comprises preparing a Compound of Formula (Ie):

wherein:

-   R^(1c), R^(2c), and R^(3c) are each independently selected from: H,     C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen;

-   comprising:

-   condensing 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one     (Compound 3A):

-   

-   with a Compound of Formula (Ic), or a salt thereof

-   

-   in the presence of a condensing-step acid and a condensing-step     solvent to form the Compound of Formula (Ie).

In some embodiments, the alkylating step further comprising preparing 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A), by the step of:

-   reacting 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A):

-   

-   with an organomagnesium reagent of 4-bromo-2-fluoro-1-methylbenzene     in the presence of a reacting-step solvent to form     2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A).

In some embodiments, the alkylating step further comprising the step of isolating 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof. In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine is the free base. In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine is crystalline. In some embodiments, wherein 4-(2-chloro-4-methoxy-5-methylphenyl)-N[1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine is crystalline Form I.

In some embodiments, the alkylating step further comprising the step of formulating 4-(2-chloro-4-methoxy-5-methylphenyl)-N[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine to form a pharmaceutical composition. In some embodiments, the step of formulating comprises admixing 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine with a pharmaceutical excipient.

In some embodiments, the alkylating step further comprises the step of isolating 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), or a pharmaceutically acceptable salt thereof.

In some embodiments, the alkylating step comprises the step of formulating 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, to form a pharmaceutical composition. In some embodiments, the step of formulating comprises admixing 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, with a pharmaceutical excipient. In some embodiments, the step of formulating comprising preparing a spray-dried dispersion as described in the examples.

In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine is the free base. In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine is crystalline. In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine is crystalline Form I.

II. Processes Useful for the Preparation of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof (Cyclizing-Step)

One aspect of the present invention relates to processes for preparing (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof:

comprising:,

-   cyclizing (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine     (Compound 6A) or a salt thereof:

-   

-   with 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one     (Compound 8A) or a tautomeric form thereof:

-   

-   in the presence of a cyclizing-step solvent to form     (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine     (Compound 9A) or a salt thereof.

In some embodiments, the tautomeric form of Compound 8A has the following chemical structure:

In some embodiments, the cyclizing-step solvent is any suitable solvent, such as, a solvent as described herein, or mixtures thereof.

In some embodiments, the cyclizing-step solvent is an aprotic solvent. In some embodiments, the cyclizing-step solvent is an aprotic solvent selected from: benzene, cyclohexane, pentane, hexane, acetonitrile, toluene, o-xylene, m-xylene, p-xylene, a mixture of xylenes, heptanes, n-heptane, octanes, n-octanes, ethylbenzene, and mixtures thereof. In some embodiments, the cyclizing-step solvent is an aprotic solvent selected from: benzene, cyclohexane, hexane, toluene, cycloheptane, o-xylene, m-xylene, p-xylene, a mixture of xylenes, heptanes, n-heptane, octanes, n-octane, ethylbenzene, and mixtures thereof. In some embodiments, the cyclizing-step solvent comprises a mixture of heptanes. In some embodiments, the cyclizing-step solvent is n-heptane.

In some embodiments, Compound 6A and Compound 8A are present in substantially equal molar quantities. In some embodiments, Compound 6A is present in a molar excess compared to Compound 8A. In some embodiments, Compound 6A is present in about 5% molar excess compared to Compound 8A. In some embodiments, Compound 6A is present in about 2% molar excess compared to Compound 8A. In some embodiments, Compound 6A is present in about 1% molar excess compared to Compound 8A.

In some embodiments, the cyclizing step further comprises the step of adding Compound 6A to a first-cyclizing mixture comprising Compound 8A and the cyclizing-step solvent at a first-cyclizing temperature.

In some embodiments, the first-cyclizing temperature is about 50° C. to about 110° C. In some embodiments, the first-cyclizing temperature is about 60° C. to about 95° C. In some embodiments, the first-cyclizing temperature is about 70° C. to about 90° C. In some embodiments, the first-cyclizing temperature is about 80° C. to about 87° C. In some embodiments, the first-cyclizing temperature is about 85° C.

In some embodiments, cyclizing is conducted with stirring.

III. Processes Useful for the Preparation (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof (Deprotecting-Step)

One aspect of the present invention relates to processes for preparing (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof:

comprising:

-   deprotecting a Compound of Formula (Ig), or a salt thereof,

-   

-   wherein: R^(1c), R^(2c), and R^(3c) are each independently selected     from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen;

-   in the presence of a deprotecting-catalyst, hydrogen, and a     deprotecting-step solvent to form     (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound     6A) or a salt thereof.

In some embodiments, the deprotecting-catalyst comprises palladium. In some embodiments, the deprotecting-catalyst comprises palladium on carbon. In some embodiments, the deprotecting-catalyst comprises about 2% palladium on carbon to about 20% palladium on carbon. In some embodiments, the deprotecting-catalyst comprises about 5% palladium on carbon to about 15% palladium on carbon. In some embodiments, the deprotecting-catalyst comprises about 10% palladium on carbon.

In some embodiments, the weight ratio between the Compound of Formula (Ig) and the deprotecting-catalyst is about 1:0.01 to about 1:0.15. In some embodiments, the weight ratio between the Compound of Formula (Ig) and the deprotecting-catalyst is about 1:0.02 to about 1:0.1. In some embodiments, the weight ratio between the Compound of Formula (Ig) and the deprotecting-catalyst is about 1:0.03 to about 1:0.07. In some embodiments, the weight ratio between the Compound of Formula (Ig) and the deprotecting-catalyst is about 1:0.05.

In some embodiments, the deprotecting-step solvent is any suitable solvent, such as, a solvent as described herein, or mixtures thereof.

In some embodiments, the deprotecting-step solvent comprises an alcohol solvent. In some embodiments, the deprotecting-step solvent comprises an alcohol solvent selected from: methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, isobutyl alcohol, 2-ethoxyethanol, 1-pentanol, 2-pentanol, 3-pentanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, and mixtures thereof. In some embodiments, the deprotecting-step solvent comprises an alcohol solvent selected from: methanol, ethanol, 1-propanol, 2-propanol, and mixtures thereof. In some embodiments, the deprotecting-step solvent comprises an alcohol solvent selected from: methanol, ethanol, and mixtures thereof. In some embodiments, the deprotecting-step solvent is methanol.

In some embodiments, the deprotecting step further comprises the steps of:

-   forming a first-deprotecting mixture comprising the Compound of     Formula (Ig), the deprotecting-catalyst, and the deprotecting-step     solvent; -   pressurizing the first-deprotecting mixture with hydrogen to form a     second-deprotecting mixture; and -   heating the second-deprotecting mixture to a first-deprotecting     temperature.

In some embodiments, pressurizing the first-deprotecting mixture with hydrogen is conducted at about 5 to about 12 bar. In some embodiments, pressurizing the first-deprotecting mixture with hydrogen is conducted at about 9 to about 11 bar. In some embodiments, pressurizing the first-deprotecting mixture with hydrogen is conducted at about 9.8 to about 10.2 bar.

In some embodiments, the first-deprotecting temperature is about 40° C. to about 80° C. In some embodiments, the first-deprotecting temperature is about 50° C. to about 70° C. In some embodiments, the first-deprotecting temperature is about 58° C. to about 62° C.

Some embodiments relate to compounds of Formula (Ig), wherein R^(1c), R^(2c), and R^(3c) are each independently selected from: H, methoxy, methyl, trifluoromethyl, fluoro, chloro, and bromo. Some embodiments relate to compounds of Formula (Ig), wherein R^(1c), R^(2c), and R^(3c) are each H (i.e., (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A)).

In some embodiments, deprotecting is conducted with stirring.

IV. Processes Useful for the Preparation of Compounds of Formula (Ig) or Salts thereof (Reducing-Step)

One aspect of the present invention relates to processes for preparing a Compound of Formula (Ig), or a salt thereof:

wherein:

-   R^(1c), R^(2c), and R^(3c) are each independently selected from: H,     C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen;

-   comprising:

-   reducing a Compound of Formula (Ie):

-   

-   in the presence of a reducing-catalyst, hydrogen, and a     reducing-step solvent to form the Compound of Formula (Ig), or a     salt thereof.

In some embodiments, the reducing-catalyst is sponge nickel or Pd/Cu—C.

In some embodiments, the reducing-catalyst is sponge nickel. In some embodiments, the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.5 to about 1:0.9. In some embodiments, the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.6 to about 1:0.8. In some embodiments, the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.65 to about 1:0.75. In some embodiments, the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.7.

In some embodiments, the reducing-catalyst is Pd/Cu—C. In some embodiments, the Pd/Cu—C catalyst comprises about 1% to about 10% Pd and about 0.2% to about 4% Cu. In some embodiments, the Pd/Cu—C catalyst comprises about 2% to about 6% Pd and about 0.5% to about 2% Cu. In some embodiments, the Pd/Cu—C catalyst comprises about 4% Pd and 1% Cu. In some embodiments, the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.01 to about 1:0.3. In some embodiments, the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.015 to about 1:0.1. In some embodiments, the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.02 to about 1:0.05. In some embodiments, the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.03.

In some embodiments, the reducing-step solvent is any suitable solvent, such as, a solvent as described herein, or mixtures thereof.

In some embodiments, the reducing-step solvent comprises an alcohol solvent. In some embodiments, the reducing-step solvent comprises an alcohol solvent selected from: methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, isobutyl alcohol, 2-ethoxyethanol, 1-pentanol, 2-pentanol, 3-pentanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, and mixtures thereof. In some embodiments, the reducing-step solvent comprises an alcohol solvent selected from: methanol, ethanol, 1-propanol, 2-propanol, and mixtures thereof. In some embodiments, the deprotecting-step solvent comprises an alcohol solvent selected from: methanol, ethanol, and mixtures thereof. In some embodiments, the reducing-step solvent comprises ethanol.

In some embodiments, the reducing step further comprises the steps of:

-   forming a first-reducing mixture comprising the reducing-catalyst     and the reducing-step solvent; -   adding the Compound of Formula (Ie) to the first-reducing mixture to     form a second-reducing mixture; -   pressurizing the second-reducing mixture with hydrogen to form a     third-reducing mixture; and -   heating the third-reducing mixture to a first-reducing temperature.

In some embodiments, adding the Compound of Formula (Ie) to the first-reducing mixture is conducted as a solution of the Compound of Formula (Ie) in toluene. In some embodiments, adding the Compound of Formula (Ie) to the first-reducing mixture is conducted as a solution of about 40% to about 80% of the Compound of Formula (Ie) in toluene. In some embodiments, adding the Compound of Formula (Ie) to the first-reducing mixture is conducted as a solution of about 50% to about 70% of the Compound of Formula (Ie) in toluene. In some embodiments, adding the Compound of Formula (Ie) to the first-reducing mixture is conducted as a solution of about 60% to about 65% of the Compound of Formula (Ie) in toluene.

In some embodiments, pressurizing the second-reducing mixture with hydrogen is conducted at about 5 to about 12 bar. In some embodiments, pressurizing the second-reducing mixture with hydrogen is conducted at about 9 to about 11 bar. In some embodiments, pressurizing the second-reducing mixture with hydrogen is conducted at about 9.8 to about 10.2 bar.

In some embodiments, the first-reducing temperature is about 25° C. to about 55° C. In some embodiments, the first-reducing temperature is about 30° C. to about 45° C. In some embodiments, the first-reducing temperature is about 33° C. to about 37° C.

Some embodiments relate to compounds of Formula (Ie), wherein R^(1c), R^(2c), and R^(3c) are each independently selected from: H, methoxy, methyl, trifluoromethyl, fluoro, chloro, and bromo. Some embodiments relate to compounds of Formula (Ie), wherein R^(1c), R^(2c), and R^(3c) are each H (i.e., (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N (1-phenylethyl)ethan-1-imine (Compound 4A)).

In some embodiments, reducing is conducted with stirring.

V. Processes Useful for the Preparation of Compounds of Formula (Ie) (Condensing-Step)

One aspect of the present invention relates to processes for preparing a Compound of Formula (Ie):

wherein:

-   R^(1c), R^(2c), and R^(3c) are each independently selected from: H,     C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen;

-   comprising:

-   condensing 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one     (Compound 3A):

-   

-   with a Compound of Formula (Ic), or a salt thereof:

-   

-   in the presence of a condensing-step acid and a condensing-step     solvent to form the Compound of Formula (Ie).

In some embodiments, the Compound of Formula (Ic) and Compound 3A are present in substantially equal molar quantities. In some embodiments, the Compound of Formula (Ic) is present in a molar excess compared to Compound 3A. In some embodiments, the molar ratio between Compound 3A and the Compound of Formula (Ic) is about 1:1 to about 1:1.5. In some embodiments, the molar ratio between Compound 3A and the Compound of Formula (Ic) is about 1:1.1 to about 1:1.3. In some embodiments, the molar ratio between Compound 3A and the Compound of Formula (Ic) is about 1:1.2.

In some embodiments, the molar ratio between Compound 3A, the Compound of Formula (Ic), and the condensing-step acid is about 1:1:0.01 to about 1:1.5:0.2. In some embodiments, the molar ratio between Compound 3A, the Compound of Formula (Ic), and the condensing-step acid is about 1:1.1:0.03 to about 1:1.3:0.1. In some embodiments, the molar ratio between Compound 3A, the Compound of Formula (Ic), and the condensing-step acid is about 1:1.2:0.05.

In some embodiments, the condensing-step acid comprises a Brønsted acid. In some embodiments, the condensing-step acid comprises a Brønsted acid selected from: acetic acid, trifluoroacetic acid (TFA), p-toluenesulfonic acid (pTSA), H₃PO₄, H₂SO₄, methanesulfonic acid (MSA), formic acid, and HCl. In some embodiments, the condensing-step acid is p-toluenesulfonic acid (pTSA).

In some embodiments, the condensing-step solvent is any suitable solvent, such as, a solvent as described herein, or mixtures thereof.

In some embodiments, the condensing-step solvent is an aprotic solvent. In some embodiments, the condensing-step solvent is an aprotic solvent selected from: benzene, cyclohexane, pentane, hexane, acetonitrile, toluene, cycloheptane, o-xylene, m-xylene, p-xylene, a mixture of xylenes, heptanes, n-heptane, octanes, n-octanes, ethylbenzene, and mixtures thereof. In some embodiments, the condensing-step solvent is acetonitrile or toluene. In some embodiments, the condensing-step solvent is acetonitrile. In some embodiments, the condensing-step solvent is toluene.

In some embodiments, condensing is conducted at the boiling point of the condensing-step solvent.

In some embodiments, condensing further comprises the removal of water. In some embodiments, condensing further comprises the removal of water using a Dean-Stark process, a desiccant, or a combination thereof. In some embodiments, condensing further comprises the removal of water using a desiccant. In some embodiments, condensing further comprises the removal of water using a Dean-Stark process.

In some embodiments, condensing further comprises the step of isolating the Compound of Formula (Ie) from a condensing-step mixture comprising the Compound of Formula (Ie) and the Compound of Formula (Ic). In some embodiments, isolating comprises substantially removing the Compound of Formula (Ic) from the condensing-step mixture using an isolating-step acid. In some embodiments, the isolating-step acid is a water-soluble acid. In some embodiments, the isolating-step acid is an ammonium halide. In some embodiments, the isolating-step acid is ammonium chloride (i.e., NH₄Cl).

Some embodiments relate to compounds of Formula (Ic), wherein R^(1c), R^(2c), and R^(3c) are each independently selected from: H, methoxy, methyl, trifluoromethyl, fluoro, chloro, and bromo. Some embodiments relate to compounds of Formula (Ic), wherein R^(1c), R^(2c), and R^(3c) are each H (i.e., (S)-(-)-1-phenylethylamine). In some embodiments, the compound of Formula (Ic) is (S)-(-)-1-phenylethylamine.

In some embodiments, condensing is conducted with stirring.

VI. Processes Useful for the Preparation of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A) (Reacting-Step)

One aspect of the present invention relates to processes for preparing 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A),

comprising:

-   reacting 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A):

-   

-   with an organomagnesium reagent of 4-bromo-2-fluoro-1-methylbenzene     in the presence of a reacting-step solvent to form     2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A).

In some embodiments, the organomagnesium reagent of 4-bromo-2-fluoro-1-methylbenzene is prepared by the process comprising the steps of:

-   forming a first-reacting mixture comprising magnesium and the     reacting-step solvent; -   adding a magnesium activator to the first-reacting mixture at a     first-reacting temperature to form a second-reacting mixture; and -   adding 4-bromo-2-fluoro-1-methylbenzene to the second-reacting     mixture at a second-reacting temperature to form the organomagnesium     reagent of 4-bromo-2-fluoro-1-methylbenzene.

In some embodiments, the first-reacting temperature is about 15° C. to about 45° C. In some embodiments, the first-reacting temperature is about 25° C. to about 40° C. In some embodiments, the first-reacting temperature is about 25° C. to about 35° C.

In some embodiments, the second-reacting temperature is about 20° C. to about 65° C. In some embodiments, the second-reacting temperature is about 25° C. to about 60° C. In some embodiments, the second-reacting temperature is about 30° C. to about 50° C.

In some embodiments, the reacting-step solvent is any suitable solvent, such as, a solvent as described herein or mixtures thereof.

In some embodiments, the reacting-step solvent is an ether solvent. In some embodiments, the reacting-step solvent is selected from: diethyl ether, 1,2-dimethoxyethane (DME), tetrahydrofuran (THF), cyclopentyl methyl ether (CPME), and 2-methyltetrahydrofuran (2-MeTHF). In some embodiments, the reacting-step solvent is selected from: tetrahydrofuran (THF), cyclopentyl methyl ether (CPME), and 2-methyltetrahydrofuran (2-MeTHF). In some embodiments, the reacting-step solvent is tetrahydrofuran (THF).

In some embodiments, the magnesium activator is I₂, 1,2-dibromoethane, diisobutylaluminium hydride (DIBAL-H), LiAlH₄, NaBH₄, sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al), and borane dimethyl sulfide complex (BH₃—SMe₂). In some embodiments, the magnesium activator is diisobutylaluminium hydride (DIBAL-H).

In some embodiments, the organomagnesium reagent of 4-bromo-2-fluoro-1-methylbenzene is:

In some embodiments, reacting is conducted with stirring.

VII. Processes Useful for the Preparation 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A) (Coupling-Step)

One aspect of the present invention relates to processes for preparing 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A),

comprising:

-   coupling 2-cyclopropylacetic acid (Compound 1A) with     N,O-dimethylhydroxylamine or a salt thereof in the presence of a     coupling-step reagent, a coupling-step base, and a coupling-step     solvent to form 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound     2A)

In some embodiments, the coupling step further comprises mixing 2-cyclopropylacetic acid (Compound 1A), the coupling-step reagent, and the coupling-step solvent together to form a first-coupling mixture.

In some embodiments, the first-coupling mixture is at a suitable first temperature to form 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A).

In some embodiments, the first-coupling mixture is at a first-coupling temperature of about -15° C. to about 35° C. In some embodiments, the first-coupling mixture is at a first-coupling temperature of about -10° C. to about 30° C. In some embodiments, the first-coupling mixture is at a first-coupling temperature of about -10° C. to about 25° C. In some embodiments, the first-coupling mixture is at a first-coupling temperature of ≤ 25° C.

In some embodiments, coupling further comprising adding N,O-dimethylhydroxylamine or a salt thereof to the first-coupling mixture to form a second-coupling mixture at a second-coupling temperature.

In some embodiments, the second-coupling temperature is ≤ 30° C. In some embodiments, the second-coupling temperature is about -15° C. to about 30° C. In some embodiments, the second-coupling temperature is about -10° C. to about 25° C. In some embodiments, the second-coupling temperature is about 20° C. to about 25° C.

In some embodiments, N,O-dimethylhydroxylamine or a salt thereof is added to the first-coupling mixture at a rate to maintain the temperature at the second-coupling temperature.

In some embodiments, the coupling step further comprises adding the coupling-step base to the second-coupling mixture.

In some embodiments, the coupling step further comprises adding the coupling-step base to the second-coupling mixture and maintaining a third-coupling temperature at about -10° C. to about 25° C. In some embodiments, the coupling step further comprising adding the coupling-step base to the second-coupling mixture and maintaining a third-coupling temperature at about 20° C. to about 25° C.

In some embodiments, the coupling-step reagent is a tetramethyluronium-based coupling reagent. In some embodiments, the coupling-step reagent is a tetramethyluronium-based coupling agent selected from: 2-(1H benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(7-aza-1Hbenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 2-(6-chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate (HCTU), and N,N,N,N-tetramethyl-O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)uranium tetrafluoroborate (TDBTU). In some embodiments, the coupling-step reagent is 1,1′-carbonyldiimidazole (CDI).

In some embodiments, the coupling-step solvent is any suitable solvent, such as, a solvent as described herein or mixtures thereof.

In some embodiments, the coupling-step solvent is an aprotic solvent. In some embodiments, the coupling-step solvent is selected from a halogenated solvent, an ether solvent, and mixtures thereof. In some embodiments, the coupling-step solvent comprises dichloromethane (DCM).

In some embodiments, the coupling-step base is a tertiary amine. In some embodiments, the coupling-step base is selected from: N,N-diisopropylethylamine (DIEA), triethylamine (TEA), N-methylmorpholine (NMM), 4-dimethylaminopyridine (DMAP), 2,4,6-trimethylpyridine (collidine), 2,3,5,6-tetramethylpyridine (TEMP), and 2,6-di-tert-butyl-4-(dimethylamino)pyridine (DBDMAP). In some embodiments, the coupling-step base is triethylamine.

In some embodiments, coupling is conducted with stirring.

Intermediate Compounds

One aspect of the present invention includes every combination of one or more compounds as described herein, and salts, solvates, and hydrates thereof.

One aspect of the present invention pertains to certain compounds of Formula (Ic):

wherein:

-   R^(1c), R^(2c), and R^(3c) are each independently selected from: H,     C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen.

Some embodiments relate to compounds of Formula (Ic), wherein R^(1c), R^(2c), and R^(3c) are each independently selected from: H, methoxy, methyl, trifluoromethyl, fluoro, chloro, and bromo.

Some embodiments relate to compounds of Formula (Ic), wherein R^(1c), R^(2c), and R^(3c) are each H (i.e., (S)-(-)-1-phenylethylamine):

One aspect of the present invention pertains to certain compounds of Formula (Ie):

wherein:

-   R^(1c), R^(2c), and R^(3c) are each independently selected from: H,     C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen.

Some embodiments relate to compounds of Formula (Ie), wherein R^(1c), R^(2c), and R^(3c) are each independently selected from: H, methoxy, methyl, trifluoromethyl, fluoro, chloro, and bromo.

Some embodiments relate to compounds of Formula (Ie), wherein R^(1c), R^(2c), and R^(3c) are each H (i.e., (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-(1-phenylethyl)ethan-1-imine (Compound 4A)):

One aspect of the present invention pertains to certain compounds of Formula (Ig):

or a salt thereof: wherein: R^(1c), R^(2c), and R^(3c) are each independently selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen.

Some embodiments relate to compounds of Formula (Ig), wherein R^(1c), R^(2c), and R^(3c) are each independently selected from: H, methoxy, methyl, trifluoromethyl, fluoro, chloro, and bromo.

Some embodiments relate to compounds of Formula (Ig), wherein R^(1c), R^(2c), and R^(3c) are each H (i.e., (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S-1-phenylethyl)ethan-1-amine (Compound SA)):

Some embodiments relate to compounds of Formula (Ig), wherein R^(1c), R^(2c), and R^(3c) are each H as the HCl salt.

Some embodiments relate to compounds of Formula (Ig), wherein R^(1c), R^(2c), and R^(3c) are each H and is an HCl salt. In some embodiments, the HCl salt is crystalline. In some embodiments, the crystalline form of the HCl salt is the crystalline (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt) as described herein.

Disorders, Uses, and Methods of Treatment

4-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) is a Corticotropin Releasing Factor 1 (CRF₁) antagonist. Accordingly, Compound 1, as the free base, a pharmaceutically acceptable salt, such as the tosylate salt, and crystal forms thereof are useful in methods of antagonizing a Corticotropin Releasing Factor 1 by contacting the receptor. In some embodiments, the contacting is conducted in vivo. In some embodiments, the contacting is conducted ex vivo. In some embodiments, Compound 1, as the free base, a pharmaceutically acceptable salt, and a crystal form thereof, can be used in methods of antagonizing Corticotropin Releasing Factor 1 in a patient in need thereof by administering an effective amount of Compound 1, as the free base, a pharmaceutically acceptable salt, or a crystal form thereof.

Methods are provided herein for treating or preventing (i.e., reducing the likelihood of occurrence) a Corticotropin Releasing Factor 1 disorder.

In some embodiments, Compound 1, pharmaceutical salts, and crystal forms thereof, are useful for the treatment or prevention of a disorder. In some embodiments, Compound 1, pharmaceutical salts, and crystal forms thereof, are useful for the treatment or prevention of a subtype of a disorder. In some embodiments, Compound 1, pharmaceutical salts, and crystal forms thereof, are useful for the treatment or prevention of a symptom of a disorder. In some embodiments, Compound 1 is a free base. In some embodiments, Compound 1 (free base) is anhydrous crystalline Form I as described herein. In some embodiments, Compound 1 is as a pharmaceutical salt, wherein the salt is a tosylate salt. In some embodiments, the Compound 1 tosylate salt is crystal Form I as described herein.

One aspect of the present invention relates to methods of treating a disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anhydrous crystalline form (Compound 1, free base) as described herein, a crystalline form (Compound 1, tosylate base) as described herein, a pharmaceutical composition as described herein, a pharmaceutical product as described herein, or a composition as described herein, wherein the subject has abnormal levels of CRF₁.

One aspect of the present invention relates to methods of treating a Corticotropin Releasing Factor 1 (CRF₁) disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anhydrous crystalline form (Compound 1, free base) as described herein, a crystalline form (Compound 1, tosylate base) as described herein, a pharmaceutical composition as described herein, a pharmaceutical product as described herein, or a composition as described herein.

One aspect of the present invention relates to methods of treating congenital adrenal hyperplasia (CAH), in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anhydrous crystalline form (Compound 1, free base) as described herein, a crystalline form (Compound 1, tosylate base) as described herein, a pharmaceutical composition as described herein, a pharmaceutical product as described herein, or a composition as described herein.

One aspect of the present invention relates to uses of an anhydrous crystalline form (Compound 1, free base) as described herein, or the crystalline form (Compound 1, tosylate base) as described herein, for the manufacture of a medicament for the treatment of a subject wherein the subject has abnormal levels of CRF₁.

One aspect of the present invention relates to uses of an anhydrous crystalline form (Compound 1, free base) as described herein, or the crystalline form (Compound 1, tosylate base) as described herein, for the manufacture of a medicament for the treatment of a Corticotropin Releasing Factor 1 (CRF₁) disorder.

One aspect of the present invention relates to uses of an anhydrous crystalline form (Compound 1, free base) as described herein, or the crystalline form (Compound 1, tosylate base) as described herein, for the manufacture of a medicament for the treatment of congenital adrenal hyperplasia (CAH).

One aspect of the present invention relates to an anhydrous crystalline form (Compound 1, free base) as described herein; a crystalline form (Compound 1, tosylate base) as described herein; a pharmaceutical composition as described herein, a pharmaceutical product as described herein, or a composition as described herein; for use in a method of treatment of the human or animal body by therapy.

One aspect of the present invention relates to an anhydrous crystalline form (Compound 1, free base) as described herein; a crystalline form (Compound 1, tosylate base) as described herein; a pharmaceutical composition as described herein; a pharmaceutical product as described herein; or a composition as described herein; for use in a method of treatment of a disorder in a subject wherein the subject has abnormal levels of CRF₁.

One aspect of the present invention relates to an anhydrous crystalline form (Compound 1, free base) as described herein; a crystalline form (Compound 1, tosylate base) as described herein; a pharmaceutical composition as described herein; a pharmaceutical product as described herein; or a composition as described herein; for use in a method of treatment of a Corticotropin Releasing Factor 1 (CRF₁) disorder.

One aspect of the present invention relates to an anhydrous crystalline form (Compound 1, free base) as described herein; a crystalline form (Compound 1, tosylate base) as described herein; a pharmaceutical composition as described herein; a pharmaceutical product as described herein; or a composition as described herein; for use in a method of treating congenital adrenal hyperplasia (CAH).

Pharmaceutical Compositions, Compositions, Formulation, and Dosage Forms

The present disclosure further provides for compositions comprising the crystalline forms of Compound 1, e.g., the free base and tosylate salt of Compound 1 as described herein, and an excipient such as a pharmaceutically acceptable excipient for use in the methods for treating Corticotropin Releasing Factor 1 (CRF₁) diseases or disorders, such as congenital adrenal hyperplasia. A pharmaceutically acceptable excipient is a physiologically and pharmaceutically suitable non-toxic and inactive material or ingredient that does not interfere with the activity of the drug substance; an excipient also may be called a carrier. The formulation methods and excipients described herein are exemplary and are in no way limiting. Pharmaceutically acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used.

For compositions formulated as liquid solutions, acceptable carriers and/or diluents include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives. The compositions can also be formulated as pills, capsules, granules, or tablets which contain, diluents, dispersing and surface active agents, binders, and lubricants. One skilled in this art may further formulate the active pharmaceutical ingredient (e.g., the free base and tosylate salt of Compound 1 as described herein) in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington, supra.

Methods of administration include systemic administration of the active pharmaceutical ingredient (e.g., the free base and tosylate salt of Compound 1 as described herein), preferably in the form of a pharmaceutical composition as discussed above. As used herein, systemic administration includes oral and parenteral methods of administration. For oral administration, suitable pharmaceutical compositions include powders, granules, pills, tablets, and capsules as well as liquids, syrups, suspensions, and emulsions. These compositions may also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives. For parental administration, the active pharmaceutical ingredient (e.g., the free base and tosylate salt of Compound 1 as described herein) can be prepared in aqueous injection solutions which may contain buffers, antioxidants, bacteriostats, and other additives commonly employed in such solutions.

Pharmaceutical preparations for oral administration can be obtained by any suitable method, typically by uniformly mixing the active pharmaceutical ingredient (e.g., the free base and tosylate salt of Compound 1 as described herein) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, processing the mixture, after adding suitable auxiliaries, if desired, forming the resulting mixture into a desired shape to obtain tablets or dragee cores.

Conventional excipients, such as binding agents, fillers, adjuvant, carrier, acceptable wetting agents, tabletting lubricants and disintegrants may be used in tablets and capsules for oral administration. Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions and syrups. Alternatively, the oral preparations may be in the form of dry powder that can be reconstituted with water or another suitable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives and flavorings and colorants may be added to the liquid preparations. Parenteral dosage forms may be prepared by dissolving the compound of the invention in a suitable liquid vehicle and filter sterilizing the solution before lyophilization, or simply filling and sealing an appropriate vial or ampule.

As used herein, an “excipient” refers to a substance that is added to a composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability, etc., to the composition. A “diluent” is a type of excipient and refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion, or inhalation. A pharmaceutically acceptable excipient is a physiologically and pharmaceutically suitable non-toxic and inactive material or ingredient that does not interfere with the activity of the drug substance. Pharmaceutically acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. For compositions formulated as liquid solutions, acceptable carriers and/or diluents include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives. In some embodiments, the diluents may be a buffered aqueous solution such as, without limitation, phosphate buffered saline. The compositions can also be formulated as capsules, granules, or tablets which contain, in addition to a compound as disclosed and described herein, diluents, dispersing and surface-active agents, binders, and lubricants. One skilled in this art may further formulate a compound as disclosed and described herein in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington, supra.

One aspect of the present invention relates to processes for preparing a pharmaceutical composition comprising admixing a crystalline form (Compound 1, free base) as described herein, a crystalline form (Compound 1, tosylate base) as described herein; or a composition as described herein, and a pharmaceutically acceptable carrier.

In making pharmaceutical compositions, the active pharmaceutical ingredient (e.g., the free base and tosylate salt of Compound 1 as described herein) is typically mixed (i.e., admixed) with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier, or medium for the drug substance. Thus, the compositions can be in the form of tablets, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

For preparing solid form pharmaceutical compositions such as powders, tablets, capsules, cachets, suppositories and dispersible granules an excipient can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the drug substance, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.

For preparing suppositories, a low melting wax, such as an admixture of fatty acid glycerides or cocoa butter, is first melted and the drug substance is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool and thereby to solidify.

Liquid form preparations include solutions, suspensions and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The pharmaceutical compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the pharmaceutical compositions may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

The pharmaceutical compositions may be formulated as an aqueous solution, an aqua-alcoholic solution, a solid suspension, an emulsion, a liposomal suspension, or a freeze-dried powder for reconstitution. Such pharmaceutical compositions may be administered directly or as an admixture for further dilution/reconstitution. Route of administration includes intravenous bolus, intravenous infusion, irrigation, and instillation. Suitable solvents include water, alcohols, PEG, propylene glycol, and lipids; pH adjustments using an acid, e.g., HCl or citric acid, can be used to increase solubility and resulting compositions subjected to suitable sterilization procedures know in the art, such as, aseptic filtration. In some embodiments, the pH of the aqueous solution is about 2.0 to about 4.0. In some embodiments, the pH of the aqueous solution is about 2.5 to about 3.5.

Aqueous formulations suitable for oral use can be prepared by dissolving or suspending the drug substance in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing the finely divided drug substance in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

For topical administration to the epidermis the active pharmaceutical ingredient (e.g., the free base and tosylate salt of Compound 1 as described herein) may be formulated as gels, ointments, creams or lotions, or as a transdermal patch. Also, formulations suitable for topical administration in the mouth include lozenges comprising drug substance in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active pharmaceutical ingredient (e.g., the free base and tosylate salt of Compound 1 as described herein) in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active pharmaceutical ingredient (e.g., the free base and tosylate salt of Compound 1 as described herein) in a suitable liquid carrier. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. In some embodiments, topical formulations can contain one or more conventional carriers. In some embodiments, ointments can contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white vaseline, and the like. Carrier compositions of creams can be based on water in combination with glycerol and one or more other components, e.g., glycerinemonostearate, PEG-glycerinemonostearate and cetylstearyl alcohol. Gels can be formulated using isopropyl alcohol and water, suitably in combination with other components such as, for example, glycerol, hydroxyethyl cellulose, and the like.

Solutions or suspensions may be applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means of an aerosol formulation provided in a pressurized pack with a suitable propellant. If administered as aerosols, for example as nasal aerosols or by inhalation, this can be carried out, for example, using a spray, a nebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaler or a dry powder inhaler. Pharmaceutical forms for administration of the active pharmaceutical ingredient (e.g., the free base and tosylate salt of Compound 1 as described herein) as an aerosol can be prepared by processes well known to the person skilled in the art. For their preparation, for example, solutions or dispersions of active pharmaceutical ingredient (e.g., the free base and tosylate salt of Compound 1 as described herein) in water, water/alcohol mixtures or suitable saline solutions can be employed using customary additives, for example benzyl alcohol or other suitable preservatives, absorption enhancers for increasing the bioavailability, solubilizers, dispersants and others and, if appropriate, customary propellants, for example include carbon dioxide, CFCs, such as, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane; and the like. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.

Alternatively, the pharmaceutical composition may be provided in the form of a dry powder, for example, a powder mix of the compound in a suitable, powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.

The active pharmaceutical ingredient (e.g., the free base and tosylate salt of Compound 1 as described herein) may also be administered via a rapid dissolving or a slow release composition, wherein the composition includes a biodegradable rapid dissolving or slow release carrier (such as a polymer carrier and the like). Rapid dissolving or slow release carriers are well known in the art and are used to form complexes that capture therein compounds of the present invention, or pharmaceutically acceptable salts thereof and either rapidly or slowly degrade/dissolve in a suitable environment (e.g., aqueous, acidic, basic, etc.).

The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions.

The compositions can be formulated in a unit dosage form, each dosage containing the drug substance or equivalent mass of the drug substance. The term “unit dosage forms” refers to physically discrete units of a formulation suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of drug substance calculated to produce the desired therapeutic effect, in association with a suitable excipient, as described herein.

The compositions described herein can be formulated to provide immediate and/or timed release (also called extended release, sustained release, controlled release, or slow release) of the active pharmaceutical ingredient (e.g., the free base and tosylate salt of Compound 1 as described herein) after administration to a subject by employing procedures known in the art. For example, the tablets can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. The tablet can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

The liquid forms can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, and similar excipients.

The pharmaceutical compositions described herein can be sterilized by conventional sterilization techniques or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations is typically between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients may result in the formation of pharmaceutically acceptable salts.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable excipients as described herein. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.

The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more-unit dosage forms containing the drug substance. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that can include a compound described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

As used herein, a “dose” or “dosage” refers to the measured quantity of drug substance to be taken at one time by a patient. In certain embodiments, wherein the drug substance is not a free base or free acid, the quantity is the molar equivalent to the corresponding amount of free base or free acid.

For preparing solid compositions such as tablets, the active pharmaceutical ingredient (e.g., the free base and tosylate salt of Compound 1 as described herein) may be mixed with an excipient to form a solid preformulation composition containing a homogeneous mixture of components. When referring to these preformulation compositions as homogeneous, the drug substance is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets and capsules.

Kits with unit doses of one or more of the compounds described herein, usually in oral or injectable doses, are provided. Such kits may include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the drugs in treating pathological condition of interest, and optionally an appliance or device for delivery of the composition.

Compounds, crystal forms, and compositions of the present invention may be effective over a wide dosage range and is generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual subject, the severity of the subject’s symptoms, and the like.

The amount of compound or composition administered to a subject will also vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the subject, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a subject already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptomology and/or pathology of the disease and its complications. Therapeutically effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the subject, and the like.

The desired dose may conveniently be presented in a single dose or presented as divided doses administered at appropriate intervals, for example, as two, three, four, or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations. The daily dose can be divided, especially when relatively large amounts are administered as deemed appropriate, into several, for example two, three, or four-part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose indicated.

Pharmaceutical Compositions and Pharmaceutical Products, Comprising Crystalline Compound 1, Free Base

One aspect of the present invention relates to pharmaceutical compositions comprising a crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base) as described herein, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is adapted for oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule. In some embodiments, the pharmaceutical composition is in the form of a tablet. In some embodiments, the pharmaceutical composition is in the form of a capsule.

One aspect of the present invention relates to pharmaceutical products selected from: a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base) as described herein.

One aspect of the present invention relates to processes for preparing pharmaceutical compositions comprising admixing a crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base) as described herein, and a pharmaceutically acceptable carrier.

Pharmaceutical Compositions and Pharmaceutical Products, Comprising Crystalline Compound 1, Tosylate Salt

One aspect of the present invention relates to pharmaceutical compositions comprising a crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt) as described herein, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is adapted for oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule. In some embodiments, the pharmaceutical composition is in the form of a tablet. In some embodiments, the pharmaceutical composition is in the form of a capsule.

One aspect of the present invention relates to pharmaceutical products selected from: a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt) as described herein.

One aspect of the present invention relates to processes for preparing pharmaceutical compositions comprising admixing a crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-Nprop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt) as described herein, and a pharmaceutically acceptable carrier.

Pharmaceutical Compositions and Pharmaceutical Products, Comprising a Compound 1 Composition

One aspect of the present invention relates to pharmaceutical compositions comprising a 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) composition as described herein, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is adapted for oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule. In some embodiments, the pharmaceutical composition is in the form of a tablet. In some embodiments, the pharmaceutical composition is in the form of a capsule.

One aspect of the present invention relates to pharmaceutical products selected from: a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a 4-(2-chloro-4-methoxy-5-methylphenyl)-N[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) composition as described herein.

One aspect of the present invention relates to processes for preparing a pharmaceutical compositions comprising admixing a 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) composition as described herein, and a pharmaceutically acceptable carrier.

One aspect of the present invention relates to processes for preparing pharmaceutical compositions comprising admixing the anhydrous crystal form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) with a pharmaceutically acceptable carrier, wherein the anhydrous crystalline form is prepared by any of the processes described herein.

Compound 1 Compositions

One aspect of the present invention relates to compositions comprising:

-   a.     4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine     (Compound 1), or a pharmaceutically acceptable salt thereof; and -   b. at least one compound selected from:     -   (S)-4-(2-Chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine         (Compound 9A);     -   (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(p-tolyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine         (Compound IIa);     -   (S)-4-(2-chloro-5-methyl-4-(prop-2-yn-1-yloxy)phenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine         (Compound IIb);     -   4-(2-chloro-4-methoxy-5-methylphenyl)-N         [(1R)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-(2-propyn-1-yl)-2-thiazolamine         (Compound IIc);     -   ethanol; and     -   propargyl bromide.

In some embodiments, the composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, has at least two compounds selected from: (S)-4-(2-Chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A); (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(p-tolyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIa); (S)-4-(2-chloro-5-methyl-4-(prop-2-yn-1-yloxy)phenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N (prop-2-yn-1-yl)thiazol-2-amine (Compound IIb); 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1R)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-(2-propyn-1-yl)-2-thiazolamine (Compound IIc); ethanol; and propargyl bromide. In some embodiments, the composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, has at least three compounds. In some embodiments, the composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, has at least four compounds. In some embodiments, the composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, has at least five compounds.

In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) is the free base.

In some embodiments, the composition contains at least 97% of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) as determined by HPLC. In some embodiments, the composition contains at least 98% of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) as determined by HPLC. In some embodiments, the composition contains at least 99% of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) as determined by HPLC.

In some embodiments, the composition contains no more than 0.3% of (S)-4-(2-Chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) as determined by HPLC. In some embodiments, the composition contains no more than 0.2% of (S)-4-(2-Chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) as determined by HPLC. In some embodiments, the composition contains no more than 0.1% of (S)-4-(2-Chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) as determined by HPLC.

In some embodiments, the composition contains no more than 0.8% of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(p-tolyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIa) as determined by HPLC. In some embodiments, the composition contains no more than 0.7% of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(p-tolyl)ethyl)-5-methyl-N (prop-2-yn-1-yl)thiazol-2-amine (Compound IIa) as determined by HPLC. In some embodiments, the composition contains no more than 0.6% of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(p-tolyl)ethyl)-5-methyl-N (prop-2-yn-1-yl)thiazol-2-amine (Compound IIa) as determined by HPLC.

In some embodiments, the composition contains no more than 0.15% of (S)-4-(2-chloro-5-methyl-4-(prop-2-yn-1-yloxy)phenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIb) as determined by HPLC. In some embodiments, the composition contains no more than 0.1% of (S)-4-(2-chloro-5-methyl-4-(prop-2-yn-1-yloxy)phenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIb) as determined by HPLC. In some embodiments, the composition contains no more than 0.05% of (S)-4-(2-chloro-5-methyl-4-(prop-2-yn-1-yloxy)phenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N (prop-2-yn-1-yl)thiazol-2-amine (Compound IIb) as determined by HPLC.

In some embodiments, the composition contains no more than 0.3% of 4-(2-chloro-4-methoxy-5-methylphenyl)-N [(1R)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N (2-propyn-1-yl)-2-thiazolamine (Compound IIc) as determined by chiral HPLC. In some embodiments, the composition contains no more than 0.2% of 4-(2-chloro-4-methoxy-5-methylphenyl)-N [(1R)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N (2-propyn-1-yl)-2-thiazolamine (Compound IIc) as determined by chiral HPLC. In some embodiments, the composition contains no more than 0.1% of 4-(2-chloro-4-methoxy-5-methylphenyl)-N [(1R)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-(2-propyn-1-yl)-2-thiazolamine (Compound IIc) as determined by chiral HPLC.

In some embodiments, the composition contains no more than 5000 ppm of ethanol as determined by gas chromatography. In some embodiments, the composition contains no more than 3000 ppm of ethanol as determined by gas chromatography. In some embodiments, the composition contains no more than 1000 ppm of ethanol as determined by gas chromatography.

In some embodiments, the composition contains no more than 200 ppm of propargyl bromide as determined by gas chromatography. In some embodiments, the composition contains no more than 100 ppm of propargyl bromide as determined by gas chromatography. In some embodiments, the composition contains no more than 30 ppm of propargyl bromide as determined by gas chromatography.

In some embodiments, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) is an anhydrous crystalline Form I as described herein.

EXAMPLES

Detailed compound synthesis methods are described in the Examples provided herein. The compounds described herein, supra and infra, are named according to MarvinSketch 18.24.0 or ChemDraw Professional 18.2.0.48. In certain instances, when common names are used, it is understood that these common names would be recognized by those skilled in the art.

The following examples are included to demonstrate embodiments of the disclosure. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

Analytical HPLC analyses were performed on an LC-MS system with a UV Detector (Dionex™ UVD 170u UV/VIS Detector), Corona array detector (Thermo™Veo™ RS), and mass spectrometer (Dionex MSQ Plus ™). Reverse-phase preparative HPLC purifications were performed on an LCMS system C18 Kinetix 5 µ100 A 150×21.2 mm column by Phenomenex using ACN/water gradient containing 0.05% TFA. All final compounds were analyzed by analytical HPLC and peaks were monitored at 210, 254 and 280 nM for purity. ¹H was recorded in an appropriate NMR solvent, such as, DMSO-d₆, on a Bruker 400 MHz spectrometer equipped with a Broad Band NMR probe. The ¹H chemical signals are given in parts per million (ppm) with the residual solvent signal used as reference. The chemical shifts are expressed in ppm (δ) and coupling constants (J) are reported in hertz (Hz). Reactions were performed under an atmosphere of dry nitrogen unless otherwise stated.

Compound 8A was previously described in International Publication Number WO2010/125414 by Sanofi-Aventis.

Example 1: Preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), See FIG. 5 for a General Synthetic Scheme Step 1A: Preparation of 2-Cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A)

A suspension of 1.1′-carbonyldiimidazole (CDI, 152.6 kg, 1.01 eq.) in DCM (682 kg, 513 L, 7.3 w/w relative to 2-cyclopropylacetic acid) was treated with a solution of 2-cyclopropylacetic acid (Compound 1A, 93.6 kg, 1 eq.) in DCM (248 kg, 186 L, 2.65 w/w) over at least 1 h, keeping the temperature ≤ 25° C. and compensating for significant effervescence. The resulting mixture was stirred for 15 min at 22° C. and then N,O-dimethylhydroxylamine•HCl1(93.6 kg, 1.03 eq.) was added in portions, keeping the temperature ≤ 30° C. Subsequently, triethylamine (46.4 kg, 0.49 eq.) was added to the stirring mixture at 20 - 25° C. The resulting mixture was stirred at 22° C. at least 1 h. The mixture was washed once with KHSO₄ solution (0.24 M, 357.1 kg, 0.09 eq.), once with KHSO₄ solution (0.40 M, 365.4 kg, 0.15 eq.), once with KHSO₄ solution (0.80 M, 384.5 kg, 0.30 eq.), and once with NaHCO3 solution (0.60 M, 393.1 kg, 0.24 eq.). Residual DCM was removed by two put-and-takes of THF (166.6 kg, 1.78 w/w) and vacuum distillation (50 - 60° C., to minimum volume/until distillation stops) to provide Compound 2A. THF (333.2 kg. 3.56 w/w) was added and the yield was determined by correcting for the LOD and GC-FID purity of the sample (131.5 kg, 98.2% corrected). ¹H-NMR (400 MHz, DMSO-d₆) δ (ppm) -0.01 - 0.03 (m, 2 H), 0.32 - 0.36 (m, 2 H), 0.81 - 0.90 (br m, 1 H), 2.18 (d, J=6.80 Hz, 2 H), 2.97 (s, 3 H), 3.53 (s, 3 H). ESI-MS: 144.0 [M+H]⁺.

Step 1B: Preparation of 2-Cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A)

Mg (turnings, 28.6 kg, 1.37 eq.) were suspended in THF (244.7 kg, 2.0 w/w) and DIBAL-H (1 M in n-heptane, 18.9 kg, 0.03 eq.) was added dropwise at 30° C. The resulting mixture was stirred at 30° C. for at least 10 min and then 4-bromo-2-fluoro-1-methylbenzene (neat, 21.1 kg, 0.13 eq.) was added over at least 30 min at 30 - 50° C. Subsequently, the mixture was treated with a solution of 4-bromo-2-fluoro-1-methylbenzene (191.6 kg, 1.18 eq.) in THF (414.5 kg, 3.37 w/w) at 30 - 50° C. over 3 h or less. The mixture was stirred at 30° C. for at least 1 h. The mixture was cooled to 12 - 18° C. and subsequently treated with 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A, 123.0 kg, 1 eq., 25.9% w/w solution in THF) over at least 1 h at 15 - 25° C. The resulting mixture was stirred at 20 - 25° C. for at least 1 h. The stirring mixture was then treated with aqueous HCl (3 M, 10.3% w/w, 668.9 kg, 2.24 eq.) at 10 - 25° C. and the resulting mixture was stirred at least 2 h until no Mg turnings were observed (check pH 3.0 - 3.5). The layers were separated, and the aqueous layer discarded. The organic layer was distilled at 55 - 65° C. and 400 mbar until distillation halts. Heptane (290.3 kg, 2.36 w/w) was added. The layers were separated, and the organic layer was washed once with NaHCO₃ solution (0.63 M, 211.6 kg, 0.15 eq.) and once with NaCl solution (2.57 M, 213.0 kg, 0.55 eq.). The residual solvents were removed by vacuum distillation at 58 - 62° C. until distillation stops and then one put-and-take of toluene (275.5 kg, 2.24 w/w) at 107 - 117° C. until distillation stops. Toluene (275.5 kg, 2.24 w/w) was added and the yield was determined by correcting for the LOD and GC-FID purity of the sample (150.7 kg, 91.3% corrected). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 0.07 - 0.21 (m, 2 H), 0.40 - 0.54 (m, 2 H), 1.02 (ttt, J=8.16, 8.16, 6.68, 6.68, 4.86, 4.86 Hz, 1 H), 2.30 (d, J=1.77 Hz, 3 H), 2.91 (d, J=6.57 Hz, 2 H), 7.44 (t, J=7.83 Hz, 1 H), 7.57 - 7.78 (m, 2 H). ESI-MS: 193.1 [M+H]⁺.

Step 1C: Preparation of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-(1-phenylethyl)ethan-1-imine (Compound 4A)

A mixture of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A, 150.7 kg, 1 eq., as a 27.6% w/w solution in toluene), (S)-(-)-1-phenylethylamine (112.9 kg, 1.19 eq.), and p-toluenesulfonic acid (7.4 kg, 0.05 eq.) was heated to reflux at 110 - 120° C. for 23 - 25 h in a reactor set up in a Dean-Stark configuration. The solvent was then removed at 125 - 135° C. under atmospheric pressure until distillation halts and a portion of toluene (275 kg, 2.24 w/w) was added to afford a suspension. The suspension was heated to reflux at 110 - 120° C. for 23 - 25 h. The mixture was cooled to 22° C. and washed twice with aqueous NH₄Cl (10%, 301.2 kg, 0.72 eq.) and once with aqueous NaHCO₃ (5%, 301.2 kg, 0.23 eq., check pH 8 - 9). The solvent was removed at 125 - 135° C. and atmospheric pressure to a target volume of 256 L, the mixture was filtered over CELITE®, and the cake was washed with toluene (25 kg). The resulting mixture containing Compound 4A was used directly in the next step without further isolation. The yield was determined by correcting for the LOD and GC-FID purity of the sample (208.4 kg, 90.0% corrected). EI-MS: 294.1 [M-H]⁺, 190.1 [M-C₆H₅CH(CH₃)1⁺, 105.1 [C₆H_(S)CH(CH₃)]⁺ •

Step 1D: Preparation of (S)-2-Cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A) as the Hydrochloride Salt

Sponge nickel catalyst (144 kg, 0.70 w/w, shipped as a 50% w/w suspension in water) was added to a hydrogenation reactor, equipped with a dip tube capable of removing material from the top of the mass inside, minimizing the amount of water introduced. The supernatant was discarded, ethanol (329.3 kg, 1.58 w/w, anhydrous) was added, the suspension was stirred and then allowed to settle. This process was repeated four more times and the supernatant is checked; <_ 1% H₂O w/w (Karl Fisher (KF)). Compound 4A (208.4 kg, 1 eq., as a 62.6% solution in toluene) was added to the mixture in the hydrogenation reactor. Ethanol (389.4 kg, 1.86 w/w) was used to rinse the addition flask into the hydrogenation reactor. The hydrogenation reactor was pressurized/depressurized twice with nitrogen (2 bar), twice with hydrogen (5 bar), and then pressurized with hydrogen (9.8 - 10.2 bar). The resulting mixture was heated to 33 - 37° C. and stirred for 17 - 19 h. The system was depressurized/pressurized three times with nitrogen (1 bar). The suspension was filtered and washed three times with ethanol (total amount, 493.8 kg, 2.37 w/w). The filtrate was combined with HC1 (concentrated, 83.4 kg, 1.07 eq.) and the resulting mixture stirred 25 - 35 min at 20 - 24° C. The mixture was concentrated by distillation at 78 - 80° C. and atmospheric pressure to remove water with a distillate target volume of 1167 L (5.6 L/kg based on imine Compound 4A) and the KF of the solution checked ≤ 1.5% H₂O w/w). The mixture was stirred at 48 - 52° C. for 55 - 65 min, then 68 -72° C. for 55 - 65 min, then cooled to 20 - 24° C. at a rate of 12° C./h and stirred for 25 - 35 min, then cooled to 0 - 4° C. at a rate of 10° C./h and stirred for 55 - 65 min. The suspension was filtered, the cake was washed twice with precooled ethanol (total amount, 329.2 kg, 1.58 w/w, 0° C.), and the collected solid was dried at 40° C. to afford Compound 5A as the HCl salt (156.5 kg, 66.4% uncorrected). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) -0.33 - -0.06 (m, 2 H), 0.11 - 0.31 (m, 3 H), 1.57 (d, J=6.57 Hz, 3 H), 1.95 (br t, J=7.07 Hz, 2 H), 2.26 (d, J=1.26 Hz, 3 H), 3.68 (br d, J=7.83 Hz, 1 H), 3.92 (br t, J=6.44 Hz, 1 H), 6.98 (dd, J=7.71, 1.14 Hz, 1 H), 7.28 - 7.36 (m, 2 H), 7.37 - 7.50 (m, 5 H). ESI-MS: 298.2 m/z [M+H]⁺.

Step 1E: Preparation of (S)-2-Cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) as the Hydrochloride Salt

Compound 5A (HCl salt, 156.5 kg, 1.00 eq.) and Pd/C (7.8 kg, 10% Pd basis) were added to an inerted hydrogenation reactor. The reactor was then pressurized/depressurized twice with nitrogen (2 bar) and then methanol (494.5 kg, 3.16 w/w) was added. The reactor was depressurized/pressurized three times with nitrogen (2 bar) then three times with hydrogen (5 bar), pressurized with hydrogen (9.8 - 10.2 bar), heated to 58 - 62° C. and stirred for 7 - 9 h. The reaction mixture was cooled to 20 - 24° C. The reactor was depressurized/pressurized three times with nitrogen (1 bar) and the suspension was filtered and washed three times with methanol (total amount, 492.9 kg, 3.15 w/w). The solution was concentrated at 63 - 67° C. and atmospheric pressure to a distillate target volume of 1408 L (9.0 L/kg Compound 6A). n-Heptane (1173.8 kg, 7.5 w/w) was added and the resulting mixture was heated to reflux at 65 - 80° C. and atmospheric pressure in Dean-Stark configuration to remove methanol. The suspension was cooled to 31 - 35° C. and filtered, the cake washed with n-heptane (147.1 kg, 0.94 w/w), and the solid dried at 40° C. to provide Compound 6A as the HCl salt (101.0 kg, 93.8% uncorrected, 99.6% ee). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) -0.12 - 0.14 (m, 2 H), 0.26 -0.42 (m, 2 H), 0.44 - 0.55 (m, 1 H), 1.70 - 1.83 (m, 2 H), 2.23 (d, J=1.52 Hz, 3 H), 4.24 (t, J=7.33 Hz, 1 H), 7.22 - 7.29 (m, 1 H), 7.29 - 7.36 (m, 1 H), 7.40 (dd, J=10.99, 1.39 Hz, 1 H). ESI-MS: 194.2 [M+H]⁺, 177.0 [M-NH₂]⁺.

Step 1F: Preparation of (S)-4-(2-Chloro-4-methoxy-S-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A)

A mixture of n-heptane (146 kg), water (142 kg), Compound 6A (HCl salt, 57.4 kg), and aqueous sodium hydroxide (30% w/w, 41.0 kg) was stirred together. The layers were partitioned, and the aqueous layer removed. The organic layer was washed with water (170 kg) and the layers partitioned. The organic layer was set aside. n-Heptane (145 kg) and 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A, 66.1 kg, the preparation of Compound 8A has been previously described in International Publication Number WO2010/125414) were added to the reactor and heated to 85° C. The previously set aside organic layer containing the free base of Compound 6A was added at 84 - 85° C. to the reactor and rinsed with n-heptane (20 kg). The resulting mixture was stirred for 2 h at 83° C. Subsequently, the solvent was switched to methanol by four put-and-take additions/vacuum distillations of methanol (180 kg) at 55° C. with the target volume being 287 L remaining in the reactor. The suspension was cooled to 5° C. and water (570 kg) was added over 4 h at 5 - 10° C., with the first 60 kg added very slowly. The suspension was aged 2 h at 5° C. and then isolated by filtration, washed with a mixture of methanol/water (91/115 kg) and then a mixture of methanol/water (134/57 kg). The yellow solid was dried at 25° C. and 1 mbar for 17 h then 40° C. and 1 mbar for 22 h to afford Compound 9A (97.4 kg, 87.5% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm -0.01 - 0.14 (m, 2 H), 0.29 - 0.42 (m, 2 H), 0.61 - 0.73 (m, 1 H), 1.47 (dt, J=13.83, 6.85 Hz, 1 H), 1.76 (dt, J=13.89, 7.20 Hz, 1 H), 2.00 (s, 3 H), 2.11 (s, 3 H), 2.19 (d, J=1.01 Hz, 3 H), 3.82 (s, 3 H), 4.54 (q, J=7.58 Hz, 1 H), 7.00 (s, 1 H), 7.06 (d, J=0.76 Hz, 1 H), 7.08 - 7.14 (m, 2 H), 7.18 - 7.23 (m, 1 H), 7.89 (d, J=8.08 Hz, 1 H). ESI-MS: 445.3 m/z [M+H]⁺.

Step 1G: Preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1)

A mixture of MTBE (279 kg), tetra-n-butylammonium bromide (10.5 kg), and Compound 9A (95.4 kg) were heated at 60° C. external temperature for 30 min and then cooled to 0° C. Aqueous potassium hydroxide (52.4% w/w, 364 kg) and propargyl bromide (39.4 kg as an 80% w/w solution in toluene, 1.19 eq.) were added at 0 - 5° C. The propargyl bromide additional funnel was washed with MTBE (25 kg) and the biphasic mixture was aged 14.5 h at 4 - 6° C. with vigorous stirring. Subsequently, water (191 kg) was added and the aqueous layer was discharged at 20° C. The organic layer was washed twice with water (382 kg) and once with aqueous acetic acid (5.26% w/w, 190 kg) at 20° C. The mixture is polish filtered, rinsed with ethanol (11 kg) and then the solvent switched to ethanol by 3 put-and-take additions/vacuum distillations of ethanol (300 kg) at 25 - 30° C. for the first cycle and then 35 - 40° C. with the target volume of each cycle being 250 L remaining in the reactor. Ethanol (164 kg) was added and the mixture heated at 60° C. external for 0.5 h before it was cooled to 25° C. in 1 h and seeded with authentic Form I (free base) of Compound 1 (0.340 kg) which can be prepared as described below in Example 2 and Example 3. The suspension was aged for 5 h, cooled to 0° C. in 2 h, aged 12 h, filtered, and washed twice with ethanol (24 kg each) pre-cooled to 0° C. The white solid was dried at 40° C. and 1 mbar for 19 h to yield 80.15 kg of Compound 1 (77.2% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 0.14 (qt, J=8.59, 4.42 Hz, 2 H), 0.29 - 0.48 (m, 2 H), 0.61 -0.82 (m, 1 H), 1.89 (dt, J=14.08, 6.98 Hz, 1 H), 2.07 (br d, J=7.83 Hz, 1 H), 2.10 (s, 3 H), 2.14 (s, 3 H), 2.20 (d, J=1.01 Hz, 3 H), 3.11 (t, J=2.27 Hz, 1 H), 3.83 (s, 3 H), 3.94 - 4.22 (m, 2 H), 5.26 (t, J=7.58 Hz, 1 H), 7.05 (s, 1 H), 7.10 - 7.36 (m, 4 H). ESI-MS: 483.2 m/z [M+H]⁺.

Example 2: Preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1)

A mixture of MTBE (2 mL), tetra-n-butylammonium bromide (110 mg), and Compound 9A (1.003 g) at 0° C. was treated with aqueous potassium hydroxide (52.4% w/w, 1.80 mL, 2.73 g) and propargyl bromide (405 mg as an 80% w/w solution in toluene) maintaining the temperature at 0 - 5° C. The resulting biphasic mixture was aged 23 h at 4 - 6° C. Subsequently, water (2 mL) and MTBE (2 mL) were added and the aqueous layer was discharged. The organic layer was washed twice with water (4 mL) and once with aqueous acetic acid (5% w/w, 2 mL) at 20° C. Ethanol (4 mL) was added and then the solvent was switched to ethanol by 3 put-and-take additions/vacuum distillations of ethanol (6 mL) at 35 - 40° C. with the target volume of each cycle being 2 mL remaining in the vessel, except for the third cycle where the mixture was concentrated to dryness. Ethanol (4 mL) was added to the vessel and the mixture heated at 60° C. (external) for 0.5 h before it was cooled to 20° C. in 1 h and aged 18 h. The resulting suspension was cooled to 0° C., aged 6 h, filtered, and washed twice with ethanol (2 mL each) pre-cooled to 0° C. to afford a solid. The solid was dried at 40° C. under vacuum to afford Compound 1 (506 mg, 46% yield) as Form I. The ¹H NMR and ESI-MS data matches that as described above in Example 1, Step 1G.

Example 3: Preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1)

A mixture of MTBE (40 mL), tetra-n-butylammonium bromide (1.1 g), and Compound 9A (10.0 g) was heated to 45° C., aged for 10 min, then cooled to 0° C. The solution was treated with aqueous potassium hydroxide (52.4% w/w, 38.2 g) and propargyl bromide (3.36 g as an 80% w/w solution in toluene) maintaining the temperature at 0 - 5° C. The resulting biphasic mixture stirred vigorously for 16 h at 4 - 6° C. Subsequently, water (20 mL) was added and the aqueous layer was discharged. The organic layer was washed twice with water (40 mL) and once with aqueous acetic acid (5.2% w/w, 20 mL) at 20° C. The solvent was switched to ethanol by 4 put-and-take additions/vacuum distillations of ethanol (15 mL) at 35 - 40° C. with the target volume of each cycle being 15 mL remaining in the vessel. The solution was weighed to approximate the amount of ethanol remaining, and ethanol (26 mL) was added to the vessel to bring the total amount of ethanol to 40 mL. The solution was cooled to 4° C. and stirred for 45 min to afford a suspension. The suspension was heated to 38° C. in 15 min, aged 10 min, then cooled to 20° C. over 14 h. The suspension was cooled to 0° C., aged 1.5 h, filtered, and the solids washed twice with ethanol (7.5 mL each) pre-cooled to 0° C. The solid was dried at 40° C. under vacuum to afford Compound 1 (8.27 g, 76% yield) as Form I. The ¹H NMR and ESI-MS data matches that as described above in Example 1, Step 1G.

The crystalline free base Compound 1, Form I was characterized by X-ray powder diffraction (XRPD) (FIG. 1 , Table 2) and DSC (FIG. 2 ). The DSC indicated the crystalline Compound 1, Form I has an onset of melt (temperature) at about 83.7° C. (76.6 J/g). The Thermogravimetric Analysis (TGA) (FIG. 2 ) of the crystalline free base exhibited substantially no weight loss (about 0.2%) from room temperature to ~125° C. indicating Form I for the free base of Compound 1 is anhydrous.

The XRPD analysis was performed on a Rigaku Powder X-Ray Diffractometer Miniflex 600 Serial Number BD66000190-01 using Cu—K α radiation and a D/teX Ultra Detector. For analysis, approximately 0.5-1 mg of Compound 1 was added to a PXRD zero-background sample holder. The powder was pressed down gently with a piece of weighing paper, and the sample holder was placed in the sample changer. Run Parameters: Miniflex Counter Detector, Kb Filter (x2), Scan Axis Theta/2-Theta, Mode Continuous, Start (deg) 2.0, Stop (deg) 45.0, Step (deg) 0.020, Speed (deg/min) 10.0, Spin-yes, Voltage (kV) 40, Current (mA) 15.

The DSC and TGA analysis were performed on TA Instruments Discovery 2500 calorimeter with serial number: 2500-00547 (DSC) and Discovery 5500 with serial number: 5500-0126 (TGA).

For TGA analysis, a standard aluminum sample pan was placed into the platinum TGA pan and the blank was tared with the instrument. Approximately 1-5 mg of Compound 1 was added to the standard aluminum pan and analyzed at 10° C./min up to 450° C.

For the DSC analysis, obtained and recorded the weight of a Tzero pan and a Tzero lid. ~1-3 mg of Compound 1 was weighed into the Tzero Pan and the Tzero lid was pressed on. The pan was transferred to the DSC autosampler for analysis. The method for analysis was a ramp at 10° C./min to 222° C. The reference pan was prepared with the same procedures, absent material.

Example 4: Gravimetric Vapor Sorption Profile for 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, Form I)

The hygroscopicity analysis for a representative sample of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, Form I) was performed on a TA Instruments Q5000 sorption analyzer with serial number 5000-5273. Approximately 3-10 mg of material was placed into a quartz crucible. The crucible was then transferred to the sorption analyzer for analysis at 25° C., with 10% RH steps not exceeding 300 minutes and with stabilization criteria of 0.10%, from 10% RH up to the maximum RH needed, then back down to 10% RH.

The Gravimetric Vapor Sorption (GVS) profile for Form I of Compound 1 as the free base is shown in FIG. 3 with corresponding data shown in Table 3.

Example 5: Preparation of (S)-2-Cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A) as the Hydrochloride Salt

Pd/Cu—C catalyst (1.22 g, 0.0033 eq., 4% Pd basis, 1% Cu basis) was added to an inerted reactor. Compound 4A (40.7 g, 1 eq., as an ~60% solution in toluene) was added and ethanol (84 mL, 106 g, 2.6 w/w) was used to rinse. The reactor was pressurized/depressurized twice with nitrogen and twice with hydrogen then pressurized with hydrogen (2 bar) and heated to 25° C. and stirred for 10.5 h. The system was depressurized/pressurized three times with nitrogen (1 bar) and the suspension was filtered and washed three times with ethanol (96 g, 2.4 w/w). The filtrate was combined with HCl (concentrated, 14.2 g, 1.07 eq.) and the resulting mixture stirred 25 - 35 min at 20 - 24° C. The mixture was concentrated by distillation at 78 - 80° C. and atmospheric pressure to remove water with a distillate target volume of 230 mL (5.6 mL/g based on imine Compound 4A) and the KF of the solution is checked ≤ 1.5% H₂O w/w). The mixture was stirred at 48 - 52° C. for 55 - 65 min, then 68 - 72° C. for 55 - 65 min, then cooled to 20 - 24° C. at a rate of 12° C./h and stirred for 25 - 35 min, then cooled to 0 - 4° C. at a rate of 10° C./h and stirred for 55 - 65 min. The suspension was filtered, the cake was washed twice with precooled ethanol (64.3 g, 1.58 w/w, 0° C.), and the solid was dried at 40° C. (26.7 g, 55.8% uncorrected) to provide Compound 5A as the HCl salt. The characterization data matches Compound 5A (HCl salt) as described above in Example 1, Step 1D.

Example 6: Preparation of (S)-4-(2-Chloro-4-(methoxy-¹³ C-d₃)-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound 3), See FIG. 4 and FIG. 6 Step 6A: Preparation of 4-Chloro-2-(methoxy-¹³C-d₃)-1-methylbenzene (Compound 7A′)

A mixture of 5-chloro-2-methylphenol (9 g, 0.063 mol., 1 equiv.) and potassium carbonate (13.21 g, 0.069 mol., 1.1 equiv.) was stirred for 15 min. at 20° C. in acetone (90 mL). A solution of iodomethane-¹³ C-d₃ in acetone (30 mL) was added over 30 minutes to the stirring mixture. The mixture was stirred at rt for 24 h and then diluted with DMF (30 mL) and stirred at rt for an additional 15 h. The acetone was removed at atmospheric pressure until all acetone is distilled off (80° C.). The remainder was combined with water (250 mL) and the resultant extracted with pentane (3 × 50 mL). The combined organic fractions were dried over Na₂SO₄, filtered to remove the solid, and concentrated under reduced pressure to afford Compound 7A′ (10.6 g, assumed quant.) as a yellow oil.

Step 6B: Preparation of 1-(2-Chloro-4-(methoxy-¹³ C-d3)-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A′)

Aluminum trichloride is charged in a 500 mL-jacketed glass reactor, then DCM is added, and the resulting mixture stirred at rt. Compound 7A′ is added to the stirring mixture over 10 minutes at rt. The resulting mixture is heated at 30° C. and stirred for 10 min. Subsequently, the mixture is cooled to 0° C. and treated with neat 2-bromopropanoyl chloride over 30 minutes. The resulting mixture is stirred at 0° C. for 20 h. Subsequently, the mixture is cooled to -5° C. and treated with water over 15 min. The resulting mixture is maintained at 0° C. and stirred for 30 min. The mixture is then combined with c-hexane and stirred overnight. The layers are then partitioned, and the organic layer is washed with water and a 1:1 mixture of 13% aq. NaCl + 5% aq. NaHCO₃. The organic layer is dried over Na₂SO₄, filtered and concentrated under reduced pressure to provide bromo intermediate. The bromo intermediate is suspended in c-hexane and filtered. The solution is concentrated and diluted with DCM. In a round bottom flask, KSCN and TBAB are dissolved in water. The aqueous mixture is heated to 55° C. and then treated over 1 h with a solution containing the bromo intermediate. The resulting mixture is stirred for 3.5 h and then water is added. The resulting mixture is stirred for 10 min. and the layers partitioned at 50° C. The organic layer is concentrated under reduced pressure and the remainder combined with methanol. The mixture is stirred at rt for 30 min. and then at 0° C. for 1 h. Solid is collected by filtration and washed with cold methanol to afford Compound 8A′.

Step 6C: Preparation of (S)-4-(2-chloro-4-(methoxy-13C-d3)-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A′)

A mixture of Compound 8A′ in heptane is heated to 90° C. and then treated with Compound 6A in heptane over 20 min. The resulting mixture is stirred at 85° C. for 5 h and then cooled to rt. The solvent is removed under reduced pressure to provide crude product. The crude product is purified by flash chromatography. The solvent is removed under reduced pressure to give Compound 9A′.

Step 6D: Preparation of (S)-4-(2-chloro-4-(methoxy-13C-d3)-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound 3)

A mixture of Compound 9A′ and TBAB in methyl tert-butyl ether at -10° C. is treated with aq. KOH (64%) over 15 min. The resulting mixture is maintained at 0° C. and treated with propargyl bromide in toluene (80%) over 10 min. The resulting mixture is stirred at 5° C. overnight and then at rt for 1 h. The mixture is combined with methyl tert-butyl ether and water. The layers are allowed to partition, and the aqueous layer is extracted with methyl tert-butyl ether. The combined organic layers are dried over Na2SO4, filtered and concentrated under reduced pressure to give an intermediate product. The intermediate product is dissolved in acetone and 37% aqueous HCl is added. The resulting mixture is stirred at 55° C. for 1 h. The mixture is cooled to rt and combined with satd. Na2CO3 followed by water. The volatiles are removed under reduced pressure and the aqueous mixture combined with methyl tert-butyl ether. The organic layer is collected, and the aqueous phase is extracted with methyl tert-butyl ether. The combined organic layers are dried over Na₂SO₄, filtered to removed solids and concentrated under reduced pressure to afford a first isolate. The first isolate is purified by column chromatography (n-hexane/MTBE 100:0 to 60:40) to afford a second isolate. The second isolate is purified by column chromatography (DCM/MTBE 100:0 to 95:5) to afford Compound 3.

Example 7: Analytical Characterization of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropy-1-1-(3-fluoro-4-methylphenyl)ethy]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1)

Four separate batches of Compound 1 were manufactured in a similar manner as described herein (i.e., Example 1) in compliance with applicable cGMPs for GLP and/or R&D use. Certain data are shown below in Table 17 for a representative batch.

TABLE 17 Tests Batch 1 Results Batch 2 Results Batch 3 Results Batch 4 Results Assay by HPLC (on dry basis), Compound 1 99.9% 97.6% 97.8% 98.4% Assay by HPLC, Compound 9A < 0.05% 0.06% n.d. n.d. Assay by HPLC, Compound IIa 0.58% 0.58% 0.52% 0.49% Assay by HPLC, Compound IIb < 0.05% n.d. n.d. n.d. Chiral purity based on Compound IIc < 0.05% n.d. n.d. n.d. Methanol (residual solvent) n.d. n.d. n.d. n.d. Heptane (residual solvent) n.d. n.d. n.d. n.d. Toluene (residual solvent) n.d. n.d. n.d. n.d. Methyl tert-butyl ether (MTBE) (residual solvent) n.d. n.d. n.d. n.d. Ethanol (residual solvent) 428 ppm 392 ppm 474 ppm 545 ppm Propargyl bromide, content ≤ 30 ppm < 1 ppm < 1 ppm < 1 ppm Propargyl alcohol, content n.d. n.d. n.d. n.d. Particle size distribution, D 10 21 µM 17 µM 16 µM 14 µM Particle size distribution, D50 129 µM 123 µM 107 µM 107 µM Particle size distribution, D90 468 µM 335 µM 320 µM 327 µM Water content 0.03% 0.03% 0.03% 0.01% n.d. = Not Detected, below limit of quantitation (LOQ).

A representative list of for specification for each of the tests used to analyze the four batches are provided below in Table 18.

TABLE 18 Tests Specifications Assay by HPLC (on dry basis), Compound 1 97.0% - 103.0% Assay by HPLC, Compound 9A (04-RORI) Max 0.3% Assay by HPLC, Compound IIa (06-RORI.i2) Max 0.8% Assay by HPLC, Compound IIb (06-RORI.i3) Max 0.15% Chiral purity based on Compound IIc (06-RORI.il) Max 0.3% Methanol (residual solvent) Max 3000 ppm Heptane (residual solvent) Max 5000 ppm Toluene (residual solvent) Max 890 ppm Methyl tert-butyl ether (MTBE) (residual solvent) Max 5000 ppm Ethanol (residual solvent) Max 5000 ppm Water content Max 0.5%

Example 8: Representative High-Performance Liquid Chromatography/High-Pressure Liquid Chromatography (HPLC) Methods for In-Process Control (IPC) and/or Assessing Purity for: 4-(2-chloro-4-methoxy-5-methylphenyl)-5-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1); (S)-4-(2-Chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A); (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(p-tolyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIa); and (S)-4-(2-chloro-5-methyl-4-(prop-2-yn-1-yloxy)phenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIb)

The sample solution in acetonitrile was injected into an Agilent 1100 HPLC System, or equivalent, with a Phenomenex, Kinetex C18 100 × 4.6 mm, 2.6 µm (P.N.: 00D-44-62-E0) and monitored by UV detection at 240 nm (BW 8, reference: off). The working concentration for the sample was about 0.25 mg/mL in acetonitrile. The positive identification for a component is established by comparing the retention time of the sample peak against the retention time for the authentic reference standard. The method conditions are presented below in Table 19:

TABLE 19 Method Conditions Gradient Elution Column Phenomenex, Kinetex C18 100 x 4.6 mm, 2.6 µm (P.N.: 00D-44-62-E0) Time %A %B Mobile Phase A TFA 0.1% in Purified Water 0 80 20 Mobile Phase B TFA 0.1% in Acetonitrile 1 80 20 Solvent Acetonitrile (CAN) 6 60 40 Flow Rate 1.2 mL/min 31 30 70 Column Temperature 30° C. 34 15 85 Auto-Sampler Temperature Ambient 37.9 15 85 Detector Wavelength 240 nm 38 80 20 Sample Injection Volume 12 µL 42 80 20 Duration 42 min

The representative retention times (t_(r), minutes) for a certain compound/intermediates were determined using the method described above and are shown in the following Table 20.

TABLE 20 Compound Representative Retention Time (t_(r)) RRT Compound 9A (04-RORI) 19.6 minutes 0.75 Compound IIa (06-RORI.i2) 23.9 minutes 0.91 Compound 1 (06-RORI) 26.3 minutes 1.00 Compound IIb (06-RORI.i3) 27.0 minutes 1.03

RRT refers to the Relative Retention Time and is the ratio of the retention time of an analyte peak (i.e., Compound 9A, Compound IIa, and Compound IIb) relative to the retention time of Compound 1 obtained under identical conditions.

Example 9: Representative Chiral High-Performance Liquid Chromatography/High-Pressure Liquid Chromatography (HPLC) Methods for In-Process Control (IPC) and/or Assessing Purity for 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1)

The sample solution in acetonitrile was injected into an Agilent 1100 HPLC System, or equivalent, with a Daicel, Chiralcel OZ-H 250 × 4.6 mm, 5 µm (P.N.: 42325), or equivalent, and monitored by UV detection at 240 nm (BW 8, reference: off). The positive identification for a component is established by comparing the retention time of the sample peak against the retention time for the authentic reference standard.

9.1 The Method Conditions Are Presented Below in Table 21

TABLE 21 Method Conditions Column Daicel, Chiralcel OZ-H 250 x 4.6 mm, 5 µm (P.N.: 42325) Mobile Phase A Hexane / Isopropanol (98/2, V/V) Gradient Isocratic elution Flow Rate 0.9 mL/min Column Temperature 25° C. Auto-Sampler Temperature Ambient Detector Wavelength 240 nm Sample Injection Volume 5 µL Duration 10 min

9.2 Preparation of “Mobile Phase A Solvent”

Hexane / Isopropanol, 98/2 (v/v), was prepared by mixing 980 mL of hexane and 20 mL of isopropanol.

9.3 Preparation of Stock Solution of Compound IIc (1 mg/mL)

The Stock Solution of Compound IIc was prepared by carefully weighing out approximately 10 mg of standard Compound IIc in a 10 mL amber flask and dissolved with approximately 5 mL of Mobile Phase A Solvent (9.2) by sonicating for 5 minutes. The resulting solution was cooled to room temperature, filled to volume with Mobile Phase A Solvent (9.2), and stir.

9.4 Preparation of Intermediate Solution of Compound IIc (0.03 mg/mL)

The intermediate solution of Compound IIc was prepared by transferring 3 mL of Stock Solution of Compound IIc (9.3) into a 100 mL amber flask, filled to volume with Mobile Phase A Solvent (9.2), and stirred.

9.5 Preparation of Resolution Solution (Compound 1: 1 mg/mL, Compound IIc: 0.003 mg/mL)

The resolution solution containing Compound 1 and Compound IIc was prepared by carefully weighing out approximately 10 mg of standard Compound 1 in a 10 mL amber flask and dissolved with approximately 5 mL of Mobile Phase A Solvent (9.2) by sonicating for 5 minutes. The resulting solution was cooled to room temperature, 1 mL of Intermediate Solution of Compound IIc (9.4) was transferred to the flask, filled to volume with Mobile Phase A Solvent (9.2), and stirred.

9.6 Preparation of Sensitivity Stock Solution of Compound 1 (1 mg/mL)

A stock solution of Compound 1 was prepared by carefully weighing out approximately 10 mg of standard Compound 1 in a 10 mL amber flask and dissolved with approximately 5 mL of Mobile Phase A Solvent (9.2) by sonicating for 5 minutes. The resulting solution was cooled to room temperature, filled to volume with Mobile Phase A Solvent (9.2), and stirred.

9.7 Preparation of Sensitivity Intermediate Solution of Compound 1 (0.01 mg/mL)

The intermediate sensitivity solution was prepared by transferring 1 mL of the Sensitivity Stock Solution of Compound 1 (9.6) to a 100 mL amber flask, filled to volume with Mobile Phase A Solvent (9.2), and stirred.

9.8 Preparation of Sensitivity Solution of Compound 1 (0.0005 mg/mL)

The “Sensitivity solution” containing was prepared by transferring 1 mL of the Sensitivity Stock Solution of Compound 1 (9.7) to a 100 mL amber flask, filled to volume with Mobile Phase A Solvent (9.2), and stirred.

9.9 Preparation of Sample for Analysis Containing Compound 1 (1 mg/mL)

The sample solution for analysis was prepared by carefully weighing out approximately 10 mg of sample containing Compound 1 in a 10 mL amber flask and dissolved with approximately 5 mL of Mobile Phase A Solvent (9.2) by sonicating for 5 minutes. The resulting solution was cooled to room temperature, filled to volume with Mobile Phase A Solvent (9.2), and stirred.

The injection sequence for the chiral analysis of Compound 1 was performed in the following consecutive order:

-   1. Mobile Phase A Solvent (9.2) at least 1 time -   2. Sensitivity Solution of Compound 1 (9.8), 1 time -   3. Resolution Solution (Compound 1 and Compound IIc) (9.5), 6 times -   4. First Sample containing Compound 1 (9.9), 1 time -   5. Second Sample containing Compound 1 (9.9), 1 time

The chiral purity for a Compound 1 sample, based on the Area % of Compound IIc present, was calculated using the area of the peaks for Compound 1 and Compound IIc and the following formula:

$\text{Compound}\,\text{IIc}\,\text{(A\%)} = \frac{Acp}{\sum A} \times 100$

Acp: Area of the Compound IIc peak in the Sample containing Compound 1 (9.9).

ΣA: Is the sum of the areas of the Compound 1 peak and the Compound IIc peak in the Sample containing Compound 1 (9.9).

100: Conversion factor %.

The representative retention times (t_(r), minutes) for a certain compound/intermediates were determined using the method described above and are shown in the following Table 22.

TABLE 22 Compound Representative Retention Time (t_(r)) RRT Compound 1 5.8 minutes 1.00 Compound IIc 5.3 minutes 0.91

RRT refers to the Relative Retention Time and is the ratio of the retention time of an analyte peak (i.e., Compound IIc) relative to the retention time of Compound 1 obtained under identical conditions.

Example 10: Headspace Gas Chromatography Method for Residual Solvents Presence in Intermediates and Compound 1

Headspace gas chromatography (HSGC) was conducted using an Agilent GC 6890 gas chromatograph equipped with Head Space injector; or equivalent, and a flame-ionization detector (FID) using an Agilent DB-624, 25 m × 0.20 mm × 1.12 µm (P.N.: 128-1324); or equivalent.

Reagents used: dimethyl sulfoxide (DMSO) for Head Space; methanol standard; ethanol standard; methyl tert-butyl ether (MTBE) standard; heptane standard; and toluene standard.

Gas Chromatography Conditions (Table 23)

TABLE 23 Parameter Conditions Column DB-624, 25 m × 0.20 mm × 1.12 µm (P.N.: 128-1324); or equivalent Initial temperature 40° C. for 3 min. Temperature program Ramp Final Temperature Waiting time 20° C. /min. 80° C. 1 min. 35° C. /min. 220° C. 4 min. Total time 14 min. Split Ratio 40:1 Inlet temperature 200° C. FID Temperature 280° C. Transport gas Nitrogen Flow 1.5 mL/min, constant flow Gas Detector Flows Air: 400 mL/min. Hydrogen: 40 mL/min. Makeup: 30 mL/min.

Headspace Conditions (Table 24)

TABLE 24 Parameter Conditions Parameter Conditions Sample Shaker High Vial pressure 15 psi Oven Temperature 100° C. Loop Fill Time 1 min. Loop Temperature 110° C. Loop Equilibration Time 0.05 min. Transfer Line Temperature 120° C. GC Cycle Time at least 28 min. Inject Time 1 min. Multi-Extraction Off Vial Equilibration Time 10 min. Vial Size 10 mL Vial Pressurization Time 0.2 min.

The GC cycle time in Table 24 is a recommendation. This can vary from instrument to instrument. The GC cycle time should be about equal to the GC run time for the GC to equilibrate to initial conditions.

Preparation of the “Standard Solution”

“Standard Stock Solutions” were prepared for the following solvents at the following concentrations in DMSO: methanol (1.5 mg/mL), ethanol (2.5 mg/mL), MTBE (2.5 mg/mL), heptane (2.5 mg/mL), and toluene (0.45 mg/mL).

The “Standard Solution” was prepared from the above standard stock solutions by transferring 1 mL of each solvent to a 10 mL flask, mixing, and filling to volume with DMSO to obtain the “Standard Solution” containing the following solvents and concentrations: methanol: 3000 ppm, ethanol: 5000 ppm, MTBE: 5000 ppm, heptane: 5000 ppm, and Toluene: 900 ppm. To a 10 mL headspace vial was transferred 0.5 mL of the resulting solution.

Compound 1 Sample Preparation

Samples of Compound 1 were prepared using 25 mg in 0.50 mL of DMSO and used as the basis for all ppm concentrations in 10 mL headspace vials. A representative headspace GC method has been published, (e.g., Dai L, et. al. (2010) LCGC North America, 28 (1), 73-84).

The injection sequence for the analysis was performed in the following consecutive order:

-   the blank (DMSO), at least 1 time; -   the “Standard Solution”, 6 times; -   the first Sample of Compound 1, 1 time; -   the second Sample of Compound 1, 1 time; and -   the “Standard Solution”, 1 time (bracketing).

The content of each solvent is calculated using the following formula:

$\text{Solvent content(ppm)=}\frac{\text{A(c)}}{\text{A(std)}} \times \frac{\text{C}\left( \text{std} \right)}{\text{P(c)}} \times 0.5 \times 1000000$

A(c) = area of the solvent of interest in the Sample

A(std) = average area of the solvent of interest for all Standard injections

C(std) = concentration of the Standard (mg/mL)

P(c) = sample weight (mg)

1000000 is the conversion factor for the unitary ratio to ppm

The retention times (t_(r), minutes) for a certain list of solvents were determined and are shown Table 25 with the limit of quantitation (LOQ) for each.

TABLE 25 Analyte t_(r) (min) LOQ (ppm) Methanol 1.7 97 Ethanol 2.3 100 MTBE 3.5 101 Heptane 5.5 101 Toluene 7.1 101

Example 11: Gas Chromatography Method for Determining Propargyl Bromide in a Sample of Compound 1

Gas chromatography (GC) was conducted using an Agilent GC 6890 gas chromatograph, or equivalent, and a flame-ionization detector (FID) using an Agilent DB-624, 25 m × 0.20 mm × 1.12 µm (P.N.: 128-1324); or equivalent.

Reagents used: dichloromethane (DCM) for HPLC, GC and residue analysis, ≥ 99.9%, stabilized with 50-150 ppm amylene; or equivalent; and propargyl bromide standard solution ~80% in Toluene

Gas Chromatography Conditions (Table 26)

TABLE 26 Parameter Conditions Column DB-624, 25 m × 0.20 mm × 1.12 µm (P.N.: 128-1324); or equivalent Initial temperature 40° C. for 3 min. Temperature program Ramp Final Temperature Waiting time 20° C. /min. 80° C. 1 min. 35° C. /min. 220° C. 10 min. Total time 20 min. Injection Volume 2 µL Liner Inert liner with glass wool, ID 4 mm (P.N. 5183-4674); or equivalent (new liner was installed prior to each analysis). Split Ratio 5:1 Inlet temperature 250° C. FID Temperature 300° C. Transport gas Nitrogen Flow 0.8 mL/min, constant flow Gas Detector Flows Air: 400 mL/min. Hydrogen: 40 mL/min. Makeup: 30 mL/min. Approximate retention time Propargyl bromide 6.5 min.

Preparation of Standard Solution

A “Standard Stock Solution” of propargyl alcohol at a concentration of 1.5 mg/mL was prepared by weighing out the equivalent of 150 mg from the propargyl bromide toluene solution (taking the titer into account) into a 100 mL flask containing an aliquot of DCM, the mixture was shaken, and filled to volume with DCM.

An “Intermediate Standard Solution” of propargyl bromide at a concentration of 0.015 mg/mL was prepared by transferring 1 mL of the above Standard Stock Solution into a 100 mL flask containing an aliquot of DCM, the mixture was shaken, and filled to volume with DCM.

A “Standard Solution” of propargyl bromide at a concentration of 0.0015 mg/mL (30 ppm) was prepared by transferring 1 mL of the above Standard Stock Solution into a 10 mL flask containing an aliquot of DCM, the mixture was shaken, and filled to volume with DCM.

A “Sensitivity Standard Solution” of propargyl bromide at a concentration of 0.050 µg/mL (1 ppm) was prepared by transferring 333 µL of the above “Standard Solution” into a 10 mL flask containing an aliquot of DCM, the mixture was shaken, and filled to volume with DCM.

Sample Preparation

A 250 mg sample of Compound 1 was carefully weighed out into a 5 mL flask, DCM was added to dissolve the sample, and filled to volume with DCM.

The injection sequence for the analysis was performed in the following consecutive order:

-   the blank (DCM), at least 2 time; -   the “Sensitivity Standard”, 1 time; -   the “Standard Solution” of propargyl bromide, 3 times; and -   the Sample of Compound 1, 1 time.

After the injection, the reporting is as follows:

-   if no peak corresponding to propargyl bromide peak in the sample of     Compound 1 was detected then the concentration of propargyl bromide     in the sample was reported as n.d. (not detected); -   if the propargyl bromide area in the sample of Compound 1 was less     the area of the “Sensitivity Standard” of propargyl bromide then the     concentration of propargyl alcohol in the sample was reported as < 1     ppm; -   if the propargyl bromide area in the sample of Compound 1 was less     than or equal to the average area of the three runs of the “Standard     Solution” of propargyl bromide then the concentration of propargyl     bromide in the sample was reported as ≤ 30 ppm; or -   if the propargyl bromide area in the sample of Compound 1 was     greater than the average area of the three runs of the “Standard     Solution” of propargyl bromide then the concentration of propargyl     bromide in the sample was reported as > 30 ppm.

Example 12: Gas Chromatography Method for Determining Propargyl Alcohol in a Sample of Compound 1

Gas chromatography (GC) was conducted using an Agilent GC 6890 gas chromatograph, or equivalent, and a flame-ionization detector (FID) using an Agilent DB-624, 25 m × 0.20 mm × 1.12 µm (P.N.: 128-1324); or equivalent.

Reagents used: dichloromethane (DCM) for HPLC, GC and residue analysis, ≥ 99.9%, stabilized with 50-150 ppm amylene; or equivalent; and propargyl alcohol standard.

Gas Chromatography Conditions (Table 27)

TABLE 27 Parameter Conditions Column DB-624, 25 m x 0.20 mm x 1.12 µm (P.N.: 128-1324); or equivalent Initial temperature 40° C. for 3 min. Temperature program Ramp Final Temperature Waiting time 20° C. /min. 80° C. 1 min. 35° C. /min. 220° C. 10 min. Total time 20 min. Injection Volume 2 µL Liner Inert liner with glass wool, ID 4 mm (P.N. 5183-4674); or equivalent (new liner was installed prior to each analysis). Split Ratio 10:1 Inlet temperature 250° C. FID Temperature 300° C. Transport gas Nitrogen Flow 0.5 mL/min, constant flow Gas Detector Flows Air: 400 mL/min. Hydrogen: 40 mL/min. Makeup: 30 mL/min. Approximate retention time Propargyl alcohol 6.1 min.

Preparation of Standard Solution

A “Standard Stock Solution” of propargyl alcohol at a concentration of 0.5 mg/mL was prepared by weighing out the equivalent of 50 mg from the propargyl alcohol into a 100 mL flask containing an aliquot of DCM, the mixture was shaken, and filled to volume with DCM.

The “Standard Solution” of propargyl alcohol at a concentration of 0.05 mg/mL (1000 ppm) was prepared by transferring 1 mL of the above Standard Stock Solution into a 10 mL flask containing an aliquot of DCM, the mixture was shaken, and filled to volume with DCM.

Sample Preparation

A 250 mg sample of Compound 1 was carefully weighed out into a 5 mL flask, DCM was added to dissolve the sample, and filled to volume with DCM.

The injection sequence for the analysis was performed in the following consecutive order:

-   the blank (DCM), at least 2 time; -   the “Standard Solution” of propargyl alcohol, 3 times; and -   the Sample of Compound 1, 1 time.

After the injection, the reporting is as follows:

-   if no peak corresponding to propargyl alcohol peak in the sample of     Compound 1 is detected then the concentration of propargyl alcohol     in the sample was reported as n.d. (not detected); -   if the propargyl alcohol area in the sample of Compound 1 was less     than or equal to the average area of the three runs of the “Standard     Solution” of propargyl alcohol then the concentration of propargyl     alcohol in the sample was reported as ≤ 1000 ppm; or -   if the propargyl alcohol area in the sample of Compound 1 was     greater than the average area of the three runs of the “Standard     Solution” of propargyl alcohol then the concentration of propargyl     alcohol in the sample was reported as > 1000 ppm.

Example 13: Spray-dried Dispersion Formulations Containing Compound 1, or Pharmaceutically Salts and/or Crystalline Forms thereof, and Various Polymers Spray-dried Dispersion Formulations

A series of spray-dried dispersion (SDD) formulations containing Compound 1 and a polymer were prepared. The SDD formulations included: (1) 10% Compound 1/90% hydroxypropylmethylcellulose acetate succinate-L (HPMCAS-L); (2) 25% Compound 1/75% HPMCAS-L; (3) 40% Compound 1/60% HPMCAS-L; (4) 25% Compound 1/75% polyvinyl pyrrolidone vinyl acetate 64 (PVP/VA 64); (5) 25% Compound 1/60% Cabosil (fumed silica)/15% HPMCAS-L; (6) 25% Compound 1/75% HPMCAS-M; and (7) 25% Compound 1/75% methyl methacrylate copolymer (1:1) (Eudragit® L100).

The PVP/VA polymer was a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate with a ratio of 60:40 by weight 1-vinyl-2-pyrrolidone:vinyl acetate with an average molecular weight of 45,000-70,000 (copovidone, sold as Kollidon® VA 64, BASF, Florham Park, NJ). The HPMCAS was a mixture of acetic acid and monosuccinic acid esters of hydroxypropylmethyl cellulose that was either grade L (HPMCAS-L), with an acetyl content of 5-9%, a succinoyl content of 14-18%, a methoxyl content of 20-24%, and a hydroxypropoxy content of 5-9% (sold by Shin-Etsu, Japan); or grade M (HPMCAS-M), with an acetyl content of 7-11%, a succinoyl content of 10-14%, a methoxyl content of 21-25%, and a hydroxypropoxy content of 5-9% (sold by Shin-Etsu, Japan).

Dissolution Performance

Dissolution performance of several of the SDD formulations described above was tested (see FIG. 19 ). 1000 µgA/mL of each SDD was tested in 0.5 wt% simulated intestinal fluid (SIF) in PBS, pH 6.5. Samples were tested at 5, 10, 20, 45, 90, and 1200 minutes. A lipid formulation containing 10% of Compound 1 was used as a control. The results are shown in Table 28, below.

TABLE 28 Dissolution data of various SDDs Sample C_(max)90 (µg/mL) AUC₉₀ (min*µg/mL) Cmax₉₀ (µg/mL) Ultra₉₀ (µg/mL) C₁₂₀₀ (µg/mL) Ultra₁₂₀₀ (µg/mL) 2 762 66,080 743 210 671 166 4 322 27,330 306 109* 268 199 6 718 62,240 708 202 632 217 7 742 60,600 742 113* 674 194 Control 802 69,580 800 253 799 270 *Large variability between replicates, high value discarded

Non-Sink Dissolution

A membrane flux assay was performed (see, e.g., Stewart et al., Mol. Pharm. (2017) 14:2032-2046) and non-sink dissolution data was collected for several of the SDD formulations described above and compared to Compound 1 and several reference formulations, including a semi-solid lipidic formulation (Reference Formulation 1) and two self-emulsifying drug delivery system (SEDDS) formulations (Reference Formulations 2 and 3). The components of the Reference Formulations are shown in Table 29, below, and include, in addition to Compound 1, caprylic/capric triglyceride (Labrafac® Lipophile, Gattefossé, France); propylene glycol dicrapolate/dicaprate (Labrafac® PG, Gattefossé, France); oleoyl polyoxyl-6 glycerides (Labrafil® M 1944 CS, Gattefossé, France); polysorbate 20; polyoxyl castor oil (Kolliphor® RH 40, BASF, Germany); polyoxyl 15 hydroxystearate (Kolliphor® HS 15, BASF, Germany); lauroyl polyoxyl-32 glycerides (Gelucire® 44/14, Gattefossé, France); d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS); and diethylene glycol monoethyl ether (Transcutol®, Gattefossé, France).

TABLE 29 Reference formulations (capsules) Formulation (mg/caps) Reference Formulation 1 Reference Formulation 2 Reference Formulation 3 Cmpd 1 50 50 50 LabrafacⓇ Lipophile 196 100 100 Labrafac® PG 102 - - Labrafil® M 1944 CS - 135 46 Polysorbate 20 - - 89.9 Kolliphor® RH 40 - - 100 Kolliphor® HS 15 - 165 - Gelucire® 44/14 95 - - TPGS 57 - 65 TranscutolⓇ - 50 50 Total 500 500 500

The assay measured the flux across simulated gastric and intestinal walls via UV spectroscopy (µDiss ProfilerTM, Pion Inc., Billerica, MA). Briefly, the assay was performed as follows. A vertical membrane flux cell consisting of a donor compartment and a receiver compartment, and separated by an Accurel PP 1E (55% porous, 100 µm thickness) polypropylene membrane (3M, Maplewood, MN) (FIG. 20 ), was impregnated with 50 µL of Pion GIT-0 lipid solution consisting of 20% w/w phospholipid dissolved into dodecane (Pion Inc., Billerica, MA) and attached to the receiver vessel. Both the donor and receiver compartments were agitated by magnetic stirring. The receiver compartment contained a plastic spacer and grating to elevate the stir bar above the membrane. Samples were introduced to the donor vessel by pre-weighing directly into the donor vessel and subsequently adding dissolution medium. Once the dissolution medium was added to the donor vessel, the receiver vessel was inserted into the donor vessel and suspended vertically 5 mm above the donor compartment by a plastic sleeve. For this assay, the simulated gastric (feed) media was 0.1 N HCl, pH 2 and included 200 µgA/mL of each SDD, and the simulated intestinal (receiver) media was 0.5 wt% SIF in PBS, pH 6.5 and included 100 µgA/mL of each SDD. The temperature for the assay was maintained at 44.5° C. UV probes (10 mm path length) connected to a Rainbow UV spectrometer (Pion Inc.) system were used to determine the apparent drug concentration in the receiver vessels. Samples of the donor compartment were removed with a disposable pipet for centrifugation followed by HPLC and DLS analysis of the supernatant. The results are shown in FIG. 21 and Table 30, below.

TABLE 30 Non-sink dissolution data Sample C_(max)GB (µg/mL) Cmax₉₀IB (µg/mL) AUC_(4-90IB) (min*µg/mL) C₉₀ (µg/mL) Ultra₉₀ (µg/mL) C₁₂₀₀ (µg/mL) Cmpd 1 0 1 10 0 0 3 1 6 80 6,800 80 79 90 2 17 74 6,240 73 73 86 4 6 4 200 4 5 36 5 23 55 3,180 55 54 83 6 35 71 6,070 71 77 83 Reference Formulation 1 205 109 9,050 109 - - Reference Formulation 2 249 120 10,160 120 - - Reference Formulation 3 218 107 9,100 107 - -

The membrane flux of 1 mg/mL gastric barrier/intestinal barrier (GB/IB) 0.5 wt% SIF doses of Compound 1 and spray-dried dispersions (2) 25% Compound 1/75% HPMCAS-L and (4) 25% Compound 1/75% PVP/VA 64 were also determined. The results are shown in FIG. 22 as receiver concentration vs. time and flux vs. time (smoothed derivative of receiver concentration × volume/surface area).

Example 14: Characterization of a Spray-dried Dispersion Containing 25% of Compound 1 and 75% of a Polyvinyl Pyrrolidone Vinyl Acetate (Pvp/Va) Polymer. SDD Stability Screening

Several of the SDDs described in Example 13 were tested for chemical and physical stability. Wet SDD stability studies were performed, with samples stored at both 5° C. and 25° C. Measurements were taken after 1 week and 2 weeks of storage. The results are shown in Table 31 below. The column with a retention time of 32.36 min correlates with Compound 1.

TABLE 31 Wet SDD stability data RT (min) 11.04 16.79 17.26 30.94 32.26 RRT 0.34 0.52 0.53 0.96 1 Storage Temp Time Point Total Impurities Ref. Std. 0.37 99.63 0.37 Cmpd 1 0.26 99.74 0.26 Sample 1 initial 0.13 0.16 0.25 99.46 0.54 5° C. 1 week 0.03 0.03 0.26 99.69 0.31 2 weeks 0.12 0.16 0.28 99.45 0.55 25° C. 1 week 0.03 0.04 0.26 99.67 0.33 2 weeks 0.21 0.27 0.28 99.24 0.76 Sample 2 initial <LOQ 0.07 0.08 0.26 99.59 0.41 5° C. 1 week <LOQ 0.02 0.03 0.26 99.7 0.3 2 weeks <LOQ 0.22 0.27 0.27 99.24 0.76 25° C. 1 week <LOQ 0.02 0.03 0.26 99.69 0.31 2 weeks <LOQ 0.23 0.28 0.26 99.23 0.77 RT = Retention Time RRT = Relative Retention Time LOQ = limit of quantification

Solution stability studies were also performed, with samples stored at both 5° C. and 25° C. Measurements were taken after 1 week and 2 weeks of storage. The results are shown in Table 32 below. The column with a retention time of 32.36 min correlates with Compound 1.

TABLE 32 SDD solution stability data RT (min) 31.51 32.26 RRT 0.97 1 Storage Temp Time Point Total Impurities Ref. Std. 0.74 99.26 0.74 Cmpd 1 0.26 99.74 0.26 Sample 1 initial 0.33 99.67 0.33 5° C. 2 weeks 0.29 99.71 0.29 25° C. 2 weeks 0.38 99.62 0.38 Sample 2 initial 0.25 99.75 0.25 5° C. 2 weeks 0.26 99.74 0.26 25° C. 2 weeks 0.33 99.67 0.33 RT = Retention Time RRT = Relative Retention Time

Stability studies were also performed for the SDD containing 25% of Compound 1 and 75% PVP/VA 64, with samples stored at both 5° C. (closed with desiccant), 25° C. (60% RH, closed with desiccant), and 30° C. (65% RH, closed with desiccant). Measurements were taken after storage for 1 month, 2 months, 3 months, 6 months, and 12 months. No change in purity was observed after 12 months of storage. The results are shown in Table 33 below. The column with a retention time of 30.2 min correlates with Compound 1.

TABLE 33 SDD stability data RT (min) 28.7 30.2 RRT 0.95 1.00 Storage Conditions Time Point Total Impurities Potency (mgA/g) Cmpd 1 (FB) Form I 0.26 99.74 0.26 1001 Sample 4 (25% Cmpd 1:75 % PVP/VA64) initial 0.26 99.74 0.26 245 5° C. (closed with desiccant) 1 month 0.25 99.75 0.25 247 2 months 0.25 99.75 0.25 244 3 months 0.26 99.74 0.26 246 6 months 0.25 99.75 0.25 245 12 months 0.25 99.75 0.25 248 25° C./60% RH (closed with desiccant) 1 month 0.25 99.75 0.25 245 2 months 0.25 99.75 0.25 247 3 months 0.25 99.75 0.25 246 6 months 0.25 99.75 0.25 242 12 months 0.25 99.75 0.25 245 30° C./65% RH (closed with desiccant) 1 month 0.25 99.75 0.25 249 2 months 0.25 99.75 0.25 242 3 months 0.25 99.75 0.25 246 6 months 0.25 99.73 0.25 243 12 months 0.25 99.75 0.25 242 RT = Retention Time RRT = Relative Retention Time

While Samples 1 and 2 showed degradation after about 2 weeks of storage, the SDD containing 25% of Compound 1 and 75% PVP/VA 64 (Sample 4) was found to be both chemically and physically stable and was further screened and characterized as described below.

25% Compound 1/75% PVP/VA 64 SDD Process Parameter Screening Manufacture Round 1

The 25% Compound 1/75% PVP/VA 64 SDD was prepared on a Pharmaceutical Spray Dryer with 100 kg/hr drying gas capacity (PSD-1). The manufacturing summary is shown in Table 34, below.

TABLE 34 Manufacturing summary of process parameters Formulation 25% Compound 1:75% PVP/VA 64 Solids Loading (wt%) 10 Batch Size (kg) 1.5 Solvent Acetone Atomizer (Pressure Swirl) SK 80-16 Solution Flow-rate (g/min) 160 Atomization Pressure (psig) 480 Inlet Temperature (°C) 94 Outlet Temperature (°C) 40 Calculated Outlet Acetone Saturation (% RS) 6.2 Dry Yield (%) 73

Based on the 73% yield observed in the first round of process screening, three sprays were performed to investigate the effect of reducing solution throughput and outlet temperature on product yield. All sprays were conducted at a reduced flow-rate of 110 g/min. The outlet temperature was varied at 40° C. (Lot A), 35° C. (Lot B), and 30° C. (Lot C). The outlet temperature was decreased while maintaining a low outlet acetone saturation to increase the difference between the chamber outlet temperature and the wet SDD Tg, thus improving product yields. The spray dryer chamber and outlet ductwork were cleaned between all manufactures. A manufacturing summary is shown in Table 35.

TABLE 35 Manufacturing summary for process parameters (1.5 kg batch size) Description Low Flow-Rate Low Flow-Rate/Low Outlet Temperature Low Flow-Rate/Lower Outlet Temperature Lot A B C Solids Loading (wt%) 10 10 10 Batch Size (kg) 1.5 1.5 1.5 Solvent Acetone Acetone Acetone Atomizer (Pressure Swirl) Steinen A75 Steinen A75 Steinen A75 Solution Flow-Rate (g/min) 110 110 110 Atomization Pressure (psig) 275 285 285 Inlet Temperature (°C) 79 72 63 Outlet Temperature (°C) 40 35 30 Calculated Outlet Acetone Saturation (% RS) 4.3 5.2 6.4 Calculated wet SDD Tg (°C) 72 71 69 Dry Yield (%) 55 80 43

The conditions used for Lot B were found to give the highest yield. One additional spray was then performed at the same processing conditions as Lot B while increasing the batch size from 1.5 kg to 3.5 kg to evaluate process consistency and to determine if product yield would continue to improve over time. The averaged process conditions for this lot are shown in Table 36.

TABLE 36 Manufacturing summary of process parameters (1.5 kg and 3.5 kg batch sizes) Description Low Flow-Rate/Low Outlet Temperature Low Flow-Rate/Lower Outlet Temperature Lot B D Solids Loading (wt%) 10 10 Batch Size (kg) 1.5 3.5 Solvent Acetone Acetone Atomizer (Pressure Swirl) Steinen A75 Steinen A75 Solution Flow-Rate (g/min) 110 110 Atomization Pressure (psig) 285 285 Inlet Temperature (°C) 72 72 Outlet Temperature (°C) 35 35 Calculated Outlet Acetone Saturation (% RS) 5.2 5.2 Calculated wet SDD Tg (°C) 71 71 Dry Yield (%) 80 84

The 1.5 kg batch size (Lot D) was sprayed with an 84% yield compared to the 80% yield of the 3.5 kg batch (Lot B).

25% Compound 1/75% PVP/VA 64 SDD Process Parameter Screening Characterization

The 25% Compound ⅟75% PVP/VA 64 SDDs manufactured to evaluate processing parameters were characterized for powder properties, performance, and physical and chemical properties. Testing included particle size distribution by Malvern, determination of bulk and tapped density, microcentrifuge dissolution, modulated differential scanning calorimetry (mDSC), powder x-ray diffraction (PXRD), scanning electron microscope (SEM), and assay and related substances. The results did not show any significant differences between the lots.

The particle size distribution (PSD) and tabulated powder properties data of the 25% Compound 1/75% PVP/VA 64 SDDs are shown in Table 37. All 25% Compound 1/75% PVP/VA 64 SDDs were observed to have a very similar PSD with a D50 of approximately 16 µm. All 25% Compound 1/75% PVP/VA 64 SDDs were observed to have low bulk and tapped densities.

TABLE 37 Powder properties of process parameter screening PVP/VA-64 SDDs Sample Lot D10 (µm) D50 (µm) D90 (µm) D(3,2) (µm) D(4,3) (µm) Span Bulk Density (g/mL) Tapped Density (g/mL) 40° C. Outlet A 5 15 34 8 17 1.93 0.12 0.25 35° C. Outlet B 5 16 36 9 19 1.97 0.11 0.23 30° C. Outlet C 5 15 32 7 17 1.86 0.12 0.27 35° C. Outlet, 3.5 kg batch D 5 16 38 9 19 1.98 0.12 0.24

The 3.5 kg batch size lot was analyzed and compared to process parameter Lot A. Dissolution performance was similar for each of these lots. Dissolution was rapid to Cmax and high free drug was sustained through 90 minutes. These data are shown in Table 38.

TABLE 38 Dissolution performance of Lot A (1.5 kg batch size) vs. Lot D (3.5 kg batch size) Sample Cmax₉₀ (µg/mL) AUC₉₀ (min*µg/mL) C₉₀ (µg/mL) Ultra₉₀ (µg/mL) Lot A 447 37,740 437 319 Lot D 437 37,120 433 301

The 25% Compound 1/75% PVP/VA 64 SDDs were also evaluated by DSC, PXRD, and SEM. The DSC thermograms showed a single Tg at 84° C., indicating homogeneous dispersions. PXRD diffractograms showed no evidence of crystals in the SDDs. SEM images showed inflated sphere morphology with some broken particles and some very small particles.

Additional testing on Lot B was carried out, which included assessing the chemical/physical stability of both spray solution and SDD prior to secondary drying (wet SDD) to establish maximum in-process hold times. Residual acetone concentration as a function of secondary drying time in a convection tray dryer was also evaluated to nominate tray drying conditions to ensure the SDD is dried below International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines for acetone.

Residual acetone content as a function of drying time was assessed by drying wet SDD in a tray dryer and collecting samples over a 24-hour period. Wet SDD was dried at 40° C./15% relative humidity (RH) and was observed to dry below ICH acetone guidelines (0.5 wt%, 5000 ppm) by four hours.

Spray solution hold time was determined by making up a representative solution that contained 2.5 wt% Compound 1, 7.5 wt% PVP/VA 64, and 90 wt% acetone. These solutions were analyzed initially for related substances. and then aged at 5° C. and 25° C. Aliquots were taken and analyzed for related substances periodically for 14 days. Results showed no change in impurity profile at either condition through 14 days.

Wet SDD was analyzed for impurities after storage at 5° C. and 25° C. for 1 and 2 weeks and compared to the impurity profiles of the ingoing Compound 1 and the SDD that was secondarily dried immediately after spray drying. The impurity profiles were similar to that of the initial dried sample and the ingoing Compound 1 through 2 weeks of storage.

The wet SDD stability samples were characterized for physical stability by DSC, PXRD, and SEM. DSC thermograms showed a single Tg at 81° C., indicative of a homogeneous dispersion with no phase separation. The PXRD diffractograms did not show any evidence of crystals after storage at either condition. SEM images showed a typical morphology of mostly inflated spheres with some broken particles.

Example 15: Preparation of a 1000 G Batch of a Spray-Dried Dispersion Containing 25% of Compound 1 and 75% PVP/VA 64

A 1000 g batch of the spray-dried dispersion containing 25% of Compound 1 and 75% PVP/VA 64 was prepared as described in Example 14 for the 1.5 kg and 3.5 kg batches. Briefly, acetone (90% (w/w) of the total mixture) was added to the mixing tank followed by the addition of 250.0 g of Compound 1 (2.5% (w/w) of the total mixture). The mixture was mixed for 30 minutes in the dark at a temperature range of 15° C. to 27° C. At the end of the mixing period, the solution was clear and free of undissolved solids. The PVP/VA 64 (750.0 g, 7.5% (w/w) of the total mixture) was then added and the mixture was stirred for an additional 30 minutes in the dark at a temperature range of 15° C. to 27° C. At the end of the mixing period, the solution was clear and free of undissolved solids.

The solution was pumped and atomized in a drying chamber. The spray-dried dispersions were prepared in a Pharmaceutical Spray Dryer with 100 kg/hr drying gas capacity (PSD-1). The inlet temperature was set at 75° C. (varied between 60° C.-90° C.). The outlet temperature was set at 35° C. (varied between 32° C.-38° C.). The feed pressure was set at 280 psig (varied between 230-330 psig). The feed rate was set at 110 g/min (varied between 90-130 g/min). The spray dried powder was then dried in a convection tray dryer with a bed depth of ≤ 2.5 cm at 40° C. (±5° C.) and 15% relative humidity (±10%) for 24 hours under amber light. The residual acetone after drying was < 0.5 wt% (5000 ppm). FIG. 23 is a flow diagram of the manufacturing process.

Example 16: Preparation of Spray-Dried Dispersion Formulations of Compound 1 for Clinical Use

The spray-dried dispersion (SDD) containing 25% Compound 1 and 75% PVP/VA 64, prepared as described above, was formulated as a suspension or a capsule for clinical use.

Suspension Preparation

A suspension that contained 50 mg of the SDD was prepared as follows. A 30 mL amber dosing bottle was tared on a balance. 200.0 mg SDD (50 mgA) ± 5% was then weighed into the dosing bottle. Using a 10-mL syringe, 5.0 mL of water (purified, USP) was added to the dosing bottle and the bottle was capped and shaken moderately for 30 seconds. The SDD suspension was stored in an amber vial at 2-8° C. prior to use, and dosed within 24 hours of preparation.

Capsule Preparation

An empty hard gelatin capsule, size 0 (Capsugel, Morristown, NJ), was placed on a balance and the weight was recorded. 200.0 mg SDD (50 mgA) ± 5% was then weighed onto weigh paper or an equivalent. All contents were transferred to the capsule using a ProFunnel device for Size 0 capsules. The filled capsule was placed on the balance and the weight was recorded. The weight of the empty capsule was subtracted from the filled weight, ensuring that the weight of the SDD within the capsule was 200.0 mg SDD ± 5%, or from 190.0 mg to 210.0 mg. The capsule was securely closed with the head, assuring it clicked into place. The capsules were stored in an amber vial at 2-8° C. prior to use, and were dosed within 24 hours of preparation.

Example 17: Compound 1 Crystalline Tosylate Salt Form 1

Approximately 20 mg of Compound 1 was weighed into a vial. Using a positive displacement pipette, 250 µL of solvent (IPA) was added to the vial along with a stir bar. The vial was placed in an aluminum block on a Reacti-Therm mixer and heated to 60° C. for ~1 hour. A molar equivalent of para-toluenesulfonic acid was added to the vial (20 µL of a 2 M solution in water) and allowed to stir. The sample was slow cooled back to room temperature along with mild Nitrogen gas for evaporation. Precipitate was collected, left to dry overnight, and then analyzed by XRPD, DSC, and TGA.

The crystallinity of the tosylate Form 1 of Compound 1 was confirmed by XRPD (FIG. 24 , Table 16) and further supported by DSC (FIG. 25 ), indicating the crystalline compound having an onset of melt at about 156° C. (22.2 J/g). TGA of the crystalline compound is provided in FIG. 28 and exhibited about 0.5% of weight loss due to solvent/H₂O.

Various modifications of the embodiments, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety. 

1. A process for preparing 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof:

comprising: alkylating (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof:

with a Compound of Formula (Ii):

wherein: LG is a leaving group; in the presence of an alkylating-step solvent, a phase-transfer catalyst, an alkylating-step base, and water to form 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof.
 2. The process according to claim 1, wherein the Compound of Formula (Ii) and Compound 9A are present in substantially equal molar quantities.
 3. The process according to claim 1, wherein the Compound of Formula (Ii) is present in a molar excess compared to Compound 9A.
 4. The process according to claim 1, wherein the Compound of Formula (Ii) is present in about 30% molar excess compared to Compound 9A.
 5. The process according to claim 1, wherein the Compound of Formula (Ii) is present in about 25% molar excess compared to Compound 9A.
 6. The process according to claim 1, wherein the Compound of Formula (Ii) is present in about 20% molar excess compared to Compound 9A.
 7. The process according to any one of claims 1 to 6, wherein Compound 9A and the phase-transfer catalyst are present in substantially equal molar quantities.
 8. The process according to any one of claims 1 to 6, wherein the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.05 to about 1:0.9.
 9. The process according to any one of claims 1 to 6, wherein the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.05 to about 1:0.8.
 10. The process according to any one of claims 1 to 6, wherein the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.05 to about 1:0.7.
 11. The process according to any one of claims 1 to 6, wherein the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.05 to about 1:0.6.
 12. The process according to any one of claims 1 to 6, wherein the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.05 to about 1:0.5.
 13. The process according to any one of claims 1 to 6, wherein the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.05 to about 1:0.4.
 14. The process according to any one of claims 1 to 6, wherein the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.1 to about 1.3:0.2.
 15. The process according to any one of claims 1 to 6, wherein the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.15.
 16. The process according to any one of claims 1 to 6, wherein the molar ratio between Compound 9A, the phase-transfer catalyst, and the alkylating-step base is about 1:0.05:5 to about 1:0.4:25.
 17. The process according to any one of claims 1 to 6, wherein the molar ratio between Compound 9A, the phase-transfer catalyst, and the alkylating-step base is about 1:0.1:10 to about 1:0.2:20.
 18. The process according to any one of claims 1 to 6, wherein the molar ratio between Compound 9A, the phase-transfer catalyst, and the alkylating-step base is about 1:0.15:16.
 19. The process according to any one of claims 1 to 18, wherein the alkylating-step solvent is selected from a halogenated solvent, an ether solvent, an aprotic solvent, and mixtures thereof.
 20. The process according to any one of claims 1 to 18, wherein the alkylating-step solvent is selected from: dichloromethane, tetrachloroethylene, 1,1-dichloroethane, 1,2-dichloroethane, 1,2-dichlorobenzene, chlorobenzene, 1,2-dimethoxyethane (DME), cyclopentyl methyl ether (CPME), 2-methyltetrahydrofuran (2-MeTHF), 1,4-dioxane, ethylene glycol diethyl ether, tert-amyl methyl ether (TAME, also referred to as 2-methoxy-2-methylbutane), methyl tert-butyl ether (MTBE), benzene, cyclohexane, hexane, toluene, cycloheptane, methylcyclohexane, heptanes, n-heptane, ethylbenzene, o-xylene, m-xylene, p-xylene, mixtures of xylenes, octane, and mixtures thereof.
 21. The process according to any one of claims 1 to 18, wherein the alkylating-step solvent is selected from: 1,2-dimethoxyethane (DME), cyclopentyl methyl ether (CPME), 2-methyltetrahydrofuran (2-MeTHF), 1,4-dioxane, ethylene glycol diethyl ether, tert-amyl methyl ether (TAME, also referred to as 2-methoxy-2-methylbutane), methyl tert-butyl ether (MTBE), benzene, toluene, and mixtures thereof.
 22. The process according to any one of claims 1 to 18, wherein the alkylating-step solvent is selected from: methyl tert-butyl ether (MTBE), toluene, and mixtures thereof.
 23. The process according to any one of claims 1 to 22, wherein the phase-transfer catalyst is a quaternary ammonium salt.
 24. The process according to any one of claims 1 to 22, wherein the phase-transfer catalyst is a quaternary ammonium salt selected from: tricaprylyl methyl ammonium chloride (Aliquat 336), tetra-n-butylammonium bromide (TBAB), benzyltriethylammonium chloride (BTEAC), cetyltrimethylammonium bromide (CTAB), tetra-n-butylammonium chloride (TBAC), tetra-n-butylammonium hydroxide, tetra-n-butylammonium iodide, tetraethylammonium chloride (TEAC), benzyltributylammonium chloride (BTBAC), cetyltrimethylammonium chloride (CTAC), tetramethylammonium chloride, cetyltrimethylammonium chloride (CTAC), octyltrimethylammonium chloride, and combinations thereof.
 25. The process according to any one of claims 1 to 22, wherein the phase-transfer catalyst is tetra-n-butylammonium bromide (TBAB).
 26. The process according to any one of claims 1 to 25, wherein the alkylating-step base is an alkali metal hydroxide.
 27. The process according to any one of claims 1 to 25, wherein the alkylating-step base is an alkali metal hydroxide selected from: lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide.
 28. The process according to any one of claims 1 to 25, wherein the alkylating-step base is an alkali metal hydroxide selected from: sodium hydroxide and potassium hydroxide.
 29. The process according to any one of claims 1 to 25, wherein the alkylating-step base is potassium hydroxide.
 30. The process according to any one of claims 1 to 29, wherein alkylating further comprises the steps of: forming a first-alkylating mixture comprising the alkylating-step solvent, the alkylating-catalyst, and Compound 9A at a first-alkylating temperature; and adding the alkylating-step base and the Compound of Formula (Ii) to the first-alkylating mixture at the first-alkylating temperature to form an alkylating-biphasic mixture at a second-alkylating temperature.
 31. The process according to claim 30, further comprising heating the first-alkylating mixture comprising the alkylating-step solvent, the alkylating-catalyst, and Compound 9A to a temperature of about 40° C. to about 75° C. and subsequently cooling to the first-alkylating temperature.
 32. The process according to claim 30, further comprising heating first-alkylating mixture comprising the alkylating-step solvent, the alkylating-catalyst, and Compound 9A to a temperature of about 55° C. to about 65° C. and subsequently cooling to the first-alkylating temperature.
 33. The process according to claim 30, further comprising heating first-alkylating mixture comprising the alkylating-step solvent, the alkylating-catalyst, and Compound 9A to a temperature of about 60° C. and subsequently cooling to the first-alkylating temperature.
 34. The process according to any one of claims 30 to 33, wherein adding the alkylating-step base to the first-alkylating mixture is conducted as a solution of the alkylating-step base in water.
 35. The process according to any one of claims 30 to 33, wherein adding the alkylating-step base to the first-alkylating mixture is conducted as a solution of the alkylating-step base in water and the concentration in terms of percent weight/weight (% w/w) of the alkylating-step base and water is about 40 to about
 60. 36. The process according to any one of claims 30 to 33, wherein adding the alkylating-step base to the first-alkylating mixture is conducted as a solution of the alkylating-step base in water and the concentration in terms of percent weight/weight (% w/w) of the alkylating-step base and water is about 45 to about
 55. 37. The process according to any one of claims 30 to 33, wherein adding the alkylating-step base to the first-alkylating mixture is conducted as a solution of the alkylating-step base in water and the concentration in terms of percent weight/weight (% w/w) of the alkylating-step base and water is about 52 to about
 53. 38. The process according to any one of claims 30 to 33, wherein adding the alkylating-step base to the first-alkylating mixture is conducted as a solution of the alkylating-step base in water and the concentration in terms of percent weight/weight (% w/w) of the alkylating-step base and water is about 52.4.
 39. The process according to any one of claims 30 to 38, wherein adding the Compound of Formula (Ii) to the first-alkylating mixture is conducted as a solution of the Compound of Formula (Ii) in the alkylating-step solvent.
 40. The process according to any one of claims 30 to 38, wherein adding the Compound of Formula (Ii) to the first-alkylating mixture is conducted as a solution of the Compound of Formula (Ii) in the alkylating-step solvent and the concentration in terms of percent weight/weight (% w/w) of the Compound of Formula (Ii) in the alkylating-step solvent is about 65 to about
 90. 41. The process according to any one of claims 30 to 38, wherein adding the Compound of Formula (Ii) to the first-alkylating mixture is conducted as a solution of the Compound of Formula (Ii) in the alkylating-step solvent and the concentration in terms of percent weight/weight (% w/w) of the Compound of Formula (Ii) in the alkylating-step solvent is about 75 to about
 85. 42. The process according to any one of claims 30 to 38, wherein adding the Compound of Formula (Ii) to the first-alkylating mixture is conducted as a solution of the Compound of Formula (Ii) in the alkylating-step solvent and the concentration in terms of percent weight/weight (% w/w) of the Compound of Formula (Ii) in the alkylating-step solvent is about
 80. 43. The process according to any one of claims 30 to 42, wherein adding the alkylating-step base and the Compound of Formula (Ii) to the first-alkylating mixture is conducted concurrently at a rate to maintain the first-alkylating temperature.
 44. The process according to any one of claims 30 to 42, wherein adding the alkylating-step base and the Compound of Formula (Ii) to the first-alkylating mixture is conducted serially at a rate to maintain the first-alkylating temperature.
 45. The process according to claim 44, wherein serially is conducted by adding the alkylating-step base followed by adding the Compound of Formula (Ii) to the first-alkylating mixture at a rate to maintain the first-alkylating temperature during each addition.
 46. The process according to any one of claims 30 to 45, wherein the first-alkylating temperature is about -15° C. to about 15° C.
 47. The process according to any one of claims 30 to 45, wherein the first-alkylating temperature is about -10° C. to about 10° C.
 48. The process according to any one of claims 30 to 45, wherein the first-alkylating temperature is about -5° C. to about 7° C.
 49. The process according to any one of claims 30 to 45, wherein the first-alkylating temperature is about 0° C. to about 5° C.
 50. The process according to any one of claims 30 to 49, wherein the second-alkylating temperature is about -10° C. to about 20° C.
 51. The process according to any one of claims 30 to 49, wherein the second-alkylating temperature is about -5° C. to about 15° C.
 52. The process according to any one of claims 30 to 49, wherein the second-alkylating temperature is about 0° C. to about 10° C.
 53. The process according to any one of claims 30 to 49, wherein the second-alkylating temperature is about 4° C. to about 6° C.
 54. The process according to any one of claims 1 to 53, wherein the LG is selected from the group: C₁-C₄ alkylsulphonyloxy, C₆-C₁₀ arylsulfonyloxy, halogen, and hydroxy; wherein C₁-C₄ alkylsulphonyloxy and C₆-C₁₀ arylsulfonyloxy are each optionally substituted with one or more groups selected from the group: C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and nitro.
 55. The process according to any one of claims 1 to 53, wherein the Compound of Formula (Ii) is a compound of the following Formula:

wherein the alkyl group is optionally substituted with one or more groups selected from the group: C ₁-C₄ alkoxy, halogen, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and nitro.
 56. The process according to claim 55, wherein the alkyl group is optionally substituted with one or more fluoro groups.
 57. The process according to claim 55, wherein the alkyl group is optionally substituted with three fluoro groups.
 58. The process according to any one of claims 1 to 53, wherein the Compound of Formula (Ii) is a compound of the following Formula:

wherein: R ^(1a), R^(2a), and R^(3a) are each selected independently from the group consisting of: H, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and nitro.
 59. The process according to claim 58, wherein R^(1a), R^(2a), and R^(3a) are each selected independently from the group consisting of: H, methyl, methoxy, fluoro, chloro, bromo, iodo, trifluoromethyl, trifluoromethoxy, and nitro.
 60. The process according to claim 58, wherein R^(1a), R^(2a), and R^(3a) are each selected independently from the group consisting of: H, methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, and nitro.
 61. The process according to claim 58, wherein R^(1a), R^(2a), and R^(3a) are each selected independently from the group consisting of: H, methyl, fluoro, trifluoromethyl, trifluoromethoxy, and nitro.
 62. The process according to claim 58, wherein R^(1a), R^(2a), and R^(3a) are each selected independently from the group consisting of: H and methyl.
 63. The process according to any one of claims 1 to 53, wherein LG is halogen.
 64. The process according to any one of claims 1 to 53, wherein LG is Cl, Br, or I.
 65. The process according to any one of claims 1 to 53, wherein LG is Br.
 66. The process according to any one of claims 1 to 53, wherein the Compound of Formula (Ii) is selected from the group consisting of: propargyl bromide, propargyl chloride, propargyl alcohol, propargyl methanesulfonate, propargyl trifluoromethanesulfonate, propargyl benzenesulfonate, and propargyl p-toluenesulfonate.
 67. The process according to any one of claims 1 to 53, wherein the Compound of Formula (Ii) is selected from the group consisting of: propargyl bromide, propargyl methanesulfonate, propargyl trifluoromethanesulfonate, propargyl benzenesulfonate, and <SHY> toluenesulfonate.
 68. The process according to any one of claims 1 to 53, wherein the Compound of Formula (Ii) is propargyl bromide.
 69. The process according to any one of claims 1 to 68, wherein alkylating is conducted with stirring.
 70. The process according to any one of claims 1 to 68, wherein alkylating is conducted with vigorous stirring.
 71. The process according to any one of claims 1 to 70, further comprising preparing (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof, by the step of: cyclizing (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof:

with 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A) or a tautomeric form thereof:

in the presence of a cyclizing-step solvent to form (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof.
 72. The process according to claim 71, further comprising preparing (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof, comprising: deprotecting a Compound of Formula (Ig), or a salt thereof:

wherein: R^(1c), R^(2c), and R^(3c) are each independently selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen; in the presence of a deprotecting-catalyst, hydrogen, and a deprotecting-step solvent to form (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof.
 73. The process according to claim 72, further comprising preparing a Compound of Formula (Ig), or a salt thereof, comprising: reducing a Compound of Formula (Ie):

wherein: R^(1c), R^(2c), and R^(3c) are each independently selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen; in the presence of a reducing-catalyst, hydrogen, and a reducing-step solvent to form the Compound of Formula (Ig), or a salt thereof.
 74. The process according to claim 73, further comprising preparing a Compound of Formula (Ie), comprising: condensing 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A):

with a Compound of Formula (Ic), or salt thereof:

wherein: R^(1c), R^(2c), and R^(3c) are each independently selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen; in the presence of a condensing-step acid and a condensing-step solvent to form the Compound of Formula (Ie).
 75. The process according to claim 74, further comprising preparing 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A), by the step of: reacting 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A):

with an organomagnesium reagent of 4-bromo-2-fluoro-1-methylbenzene in the presence of a reacting-step solvent to form 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A).
 76. The process according to any one of claims 1 to 75, further comprising the step of isolating 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), or a pharmaceutically acceptable salt thereof.
 77. The process according to any one of claims 1 to 76, further comprising the step of formulating 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), or a pharmaceutically acceptable salt thereof, to form a pharmaceutical composition.
 78. The process according to claim 77, wherein the step of formulating comprises admixing 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, with a pharmaceutical excipient.
 79. The process according to any one of claims 1 to 78, wherein 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) is the free base.
 80. The process according to any one of claims 1 to 79, wherein 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) is crystalline.
 81. The process according to any one of claims 1 to 80, wherein 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) is anhydrous crystalline Form I.
 82. A process for preparing (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof:

comprising: cyclizing (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof:

with 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A) or a tautomeric form thereof:

in the presence of a cyclizing-step solvent to form (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N (2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof.
 83. The process according to claim 82, wherein the cyclizing-step solvent is an aprotic solvent.
 84. The process according to claim 82, wherein the cyclizing-step solvent is an aprotic solvent selected from: benzene, cyclohexane, pentane, hexane, acetonitrile, toluene, o-xylene, m-xylene, p-xylene, a mixture of xylenes, heptanes, n-heptane, octanes, n-octanes, ethylbenzene, and mixtures thereof.
 85. The process according to claim 82, wherein the cyclizing-step solvent is an aprotic solvent selected from: benzene, cyclohexane, hexane, toluene, cycloheptane, o-xylene, m-xylene, p-xylene, a mixture of xylenes, heptanes, n-heptane, octanes, n-octane, ethylbenzene, and mixtures thereof.
 86. The process according to claim 82, wherein the cyclizing-step solvent comprises a mixture of heptanes.
 87. The process according to claim 82, wherein the cyclizing-step solvent is n-heptane.
 88. The process according to any one of claims 82 to 87, wherein Compound 6A and Compound 8A are present in substantially equal molar quantities.
 89. The process according to any one of claims 82 to 87, wherein Compound 6A is present in a molar excess compared to Compound 8A.
 90. The process according to any one of claims 82 to 87, wherein Compound 6A is present in about 5% molar excess compared to Compound 8A.
 91. The process according to any one of claims 82 to 87, wherein Compound 6A is present in about 2% molar excess compared to Compound 8A.
 92. The process according to any one of claims 82 to 87, wherein Compound 6A is present in about 1% molar excess compared to Compound 8A.
 93. The process according to any one of claims 82 to 92, wherein cyclizing further comprises the step of adding Compound 6A to a first-cyclizing mixture comprising Compound 8A and the cyclizing-step solvent at a first-cyclizing temperature.
 94. The process according to claim 93, wherein the first-cyclizing temperature is about 50° C. to about 110° C.
 95. The process according to claim 93, wherein the first-cyclizing temperature is about 60° C. to about 95° C.
 96. The process according to claim 93, wherein the first-cyclizing temperature is about 70° C. to about 90° C.
 97. The process according to claim 93, wherein the first-cyclizing temperature is about 80° C. to about 87° C.
 98. The process according to claim 93, wherein the first-cyclizing temperature is about 85° C.
 99. The process according to any one of claims 82 to 98, wherein cyclizing is conducted with stirring.
 100. A process for preparing (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof:

comprising: deprotecting a Compound of Formula (Ig), or a salt thereof:

wherein: R^(1c), R^(2c), and R^(3c) are each independently selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen; in the presence of a deprotecting-catalyst, hydrogen, and a deprotecting-step solvent to form (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof.
 101. The process according to claim 100, wherein the deprotecting-catalyst comprises palladium.
 102. The process according to claim 100, wherein the deprotecting-catalyst comprises palladium on carbon.
 103. The process according to claim 100, wherein the deprotecting-catalyst comprises about 2% palladium on carbon to about 20% palladium on carbon.
 104. The process according to claim 100, wherein the deprotecting-catalyst comprises about 5% palladium on carbon to about 15% palladium on carbon.
 105. The process according to claim 100, wherein the deprotecting-catalyst comprises about 10% palladium on carbon.
 106. The process according to any one of claims 100 to 105, wherein the weight ratio between the Compound of Formula (Ig) and the deprotecting-catalyst is about 1:0.01 to about 1:0.15.
 107. The process according to any one of claims 100 to 105, wherein the weight ratio between the Compound of Formula (Ig) and the deprotecting-catalyst is about 1:0.02 to about 1:0.1.
 108. The process according to any one of claims 100 to 105, wherein the weight ratio between the Compound of Formula (Ig) and the deprotecting-catalyst is about 1:0.03 to about 1:0.07.
 109. The process according to any one of claims 100 to 105, wherein the weight ratio between the Compound of Formula (Ig) and the deprotecting-catalyst is about 1:0.05.
 110. The process according to any one of claims 100 to 109, wherein the deprotecting-step solvent comprises an alcohol solvent.
 111. The process according to any one of claims 100 to 109, wherein the deprotecting-step solvent comprises an alcohol solvent selected from: methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, isobutyl alcohol, 2-ethoxyethanol, 1-pentanol, 2-pentanol, 3-pentanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, and mixtures thereof.
 112. The process according to any one of claims 100 to 109, wherein the deprotecting-step solvent comprises an alcohol solvent selected from: methanol, ethanol, 1-propanol, 2-propanol, and mixtures thereof.
 113. The process according to any one of claims 100 to 109, wherein the deprotecting-step solvent comprises an alcohol solvent selected from: methanol, ethanol, and mixtures thereof.
 114. The process according to any one of claims 100 to 109, wherein the deprotecting-step solvent is methanol.
 115. The process according to any one of claims 100 to 114, wherein deprotecting further comprises the steps of: forming a first-deprotecting mixture comprising the Compound of Formula (Ig), the deprotecting-catalyst, and the deprotecting-step solvent; pressurizing the first-deprotecting mixture with hydrogen to form a second-deprotecting mixture; and heating the second-deprotecting mixture to a first-deprotecting temperature.
 116. The process according to claim 115, wherein pressurizing the first-deprotecting mixture with hydrogen is conducted at about 5 to about 12 bar.
 117. The process according to claim 115, wherein pressurizing the first-deprotecting mixture with hydrogen is conducted at about 9 to about 11 bar.
 118. The process according to claim 115, wherein pressurizing the first-deprotecting mixture with hydrogen is conducted at about 9.8 to about 10.2 bar.
 119. The process according to any one of claims 115 to 118, wherein the first-deprotecting temperature is about 40° C. to about 80° C.
 120. The process according to any one of claims 115 to 118, wherein the first-deprotecting temperature is about 50° C. to about 70° C.
 121. The process according to any one of claims 115 to 118, wherein the first-deprotecting temperature is about 58° C. to about 62° C.
 122. The process according to any one of claims 100 to 121, wherein R^(1c), R^(2c), and R^(3c) are each independently selected from: H, methoxy, methyl, trifluoromethyl, fluoro, chloro, and bromo.
 123. The process according to any one of claims 100 to 121, wherein R^(1c), R^(2c), and R^(3c) are each H.
 124. The process according to any one of claims 100 to 123, wherein deprotecting is conducted with stirring.
 125. A process for preparing a Compound of Formula (Ig), or a salt thereof:

wherein: R^(1c), R^(2c), and R^(3c) are each independently selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen; comprising: reducing a Compound of Formula (Ie):

in the presence of a reducing-catalyst, hydrogen, and a reducing-step solvent to form the Compound of Formula (Ig), or a salt thereof.
 126. The process according to claim 125, wherein the reducing-catalyst is sponge nickel or Pd/Cu—C.
 127. The process according to claim 125, wherein the reducing-catalyst is sponge nickel.
 128. The process according to claim 125, wherein the reducing-catalyst is Pd/Cu—C.
 129. The process according to claim 128, wherein the Pd/Cu—C catalyst comprises about 1% to about 10% Pd and about 0.2% to about 4% Cu.
 130. The process according to claim 128, wherein the Pd/Cu—C catalyst comprises about 2% to about 6% Pd and about 0.5% to about 2% Cu.
 131. The process according to claim 128, wherein the Pd/Cu—C catalyst comprises about 4% Pd and 1% Cu.
 132. The process according to claim 127, wherein the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.5 to about 1:0.9.
 133. The process according to claim 127, wherein the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.6 to about 1:0.8.
 134. The process according to claim 127, wherein the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.65 to about 1:0.75.
 135. The process according to claim 127, wherein the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.7.
 136. The process according to any one of claims 128 to 131, wherein the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.01 to about 1:0.3.
 137. The process according to any one of claims 128 to 131, wherein the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.015 to about 1:0.1.
 138. The process according to any one of claims 128 to 131, wherein the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.02 to about 1:0.05.
 139. The process according to any one of claims 128 to 131, wherein the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.03.
 140. The process according to any one of claims 125 to 139, wherein the reducing-step solvent comprises an alcohol solvent.
 141. The process according to any one of claims 125 to 139, wherein the reducing-step solvent comprises an alcohol solvent selected from: methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, isobutyl alcohol, 2-ethoxyethanol, 1-pentanol, 2-pentanol, 3-pentanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, and mixtures thereof.
 142. The process according to any one of claims 125 to 139, wherein the reducing-step solvent comprises an alcohol solvent selected from: methanol, ethanol, 1-propanol, 2-propanol, and mixtures thereof.
 143. The process according to any one of claims 125 to 139, wherein the deprotecting-step solvent comprises an alcohol solvent selected from: methanol, ethanol, and mixtures thereof.
 144. The process according to any one of claims 125 to 139, wherein the reducing-step solvent comprises ethanol.
 145. The process according to any one of claims 125 to 144, wherein reducing further comprises the steps of:6 forming a first-reducing mixture comprising the reducing-catalyst and the reducing-step solvent; adding the Compound of Formula (Ie) to the first-reducing mixture to form a second-reducing mixture; pressurizing the second-reducing mixture with hydrogen to form a third-reducing mixture; and heating the third-reducing mixture to a first-reducing temperature.
 146. The process according to claim 145, wherein adding the Compound of Formula (Ie) to the first-reducing mixture is conducted as a solution of the Compound of Formula (Ie) in toluene.
 147. The process according to claim 145, wherein adding the Compound of Formula (Ie) to the first-reducing mixture is conducted as a solution of about 40% to about 80% of the Compound of Formula (Ie) in toluene.
 148. The process according to claim 145, wherein adding the Compound of Formula (Ie) to the first-reducing mixture is conducted as a solution of about 50% to about 70% of the Compound of Formula (Ie) in toluene.
 149. The process according to claim 145, wherein adding the Compound of Formula (Ie) to the first-reducing mixture is conducted as a solution of about 60% to about 65% of the Compound of Formula (Ie) in toluene.
 150. The process according to any one of claims 145 to 149, wherein pressurizing the second-reducing mixture with hydrogen is conducted at about 5 to about 12 bar.
 151. The process according to any one of claims 145 to 149, wherein pressurizing the second-reducing mixture with hydrogen is conducted at about 9 to about 11 bar.
 152. The process according to any one of claims 145 to 149, wherein pressurizing the second-reducing mixture with hydrogen is conducted at about 9.8 to about 10.2 bar.
 153. The process according to any one of claims 145 to 152, wherein the first-reducing temperature is about 25° C. to about 55° C.
 154. The process according to any one of claims 145 to 152, wherein the first-reducing temperature is about 30° C. to about 45° C.
 155. The process according to any one of claims 145 to 152, wherein the first-reducing temperature is about 33° C. to about 37° C.
 156. The process according to any one of claims 125 to 155, wherein R^(1c), R^(2c), and R^(3c) are each independently selected from: H, methoxy, methyl, trifluoromethyl, fluoro, chloro, and bromo.
 157. The process according to any one of claims 125 to 155, wherein R^(1c), R^(2c), and R^(3c) are each H.
 158. The process according to any one of claims 125 to 157, wherein reducing is conducted with stirring.
 159. A process for preparing a Compound of Formula (Ie):

wherein: R^(1c), R^(2c), and R^(3c) are each independently selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen; comprising: condensing 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A):

with a Compound of Formula (Ic), or a salt thereof:

in the presence of a condensing-step acid and a condensing-step solvent to form the Compound of Formula (Ie).
 160. The process according to claim 159, wherein the Compound of Formula (Ic) and Compound 3A are present in substantially equal molar quantities.
 161. The process according to claim 159, wherein the Compound of Formula (Ic) is present in a molar excess compared to Compound 3A.
 162. The process according to claim 159, wherein the molar ratio between Compound 3A and the Compound of Formula (Ic) is about 1:1 to about 1:1.5.
 163. The process according to claim 159, wherein the molar ratio between Compound 3A and the Compound of Formula (Ic) is about 1:1.1 to about 1:1.3.
 164. The process according to claim 159, wherein the molar ratio between Compound 3A and the Compound of Formula (Ic) is about 1:1.2.
 165. The process according to claim 159, wherein the molar ratio between Compound 3A, the Compound of Formula (Ic), and the condensing-step acid is about 1:1:0.01 to about 1:1.5:0.2.
 166. The process according to claim 159, wherein the molar ratio between Compound 3A, the Compound of Formula (Ic), and the condensing-step acid is about 1:1.1:0.03 to about 1:1.3:0.1.
 167. The process according to claim 159, wherein the molar ratio between Compound 3A, the Compound of Formula (Ic), and the condensing-step acid is about 1:1.2:0.05.
 168. The process according to any one of claims 159 to 167, wherein the condensing-step acid comprises a Brønsted acid.
 169. The process according to any one of claims 159 to 167, wherein the condensing-step acid comprises a Brønsted acid selected from: acetic acid, trifluoroacetic acid (TFA), p-toluenesulfonic acid (pTSA), H₃PO₄, H₂SO₄, methanesulfonic acid (MSA), formic acid, and HCl.
 170. The process according to any one of claims 159 to 167, wherein the condensing-step acid is p-toluenesulfonic acid (pTSA).
 171. The process according to any one of claims 159 to 170, wherein the condensing-step solvent is an aprotic solvent.
 172. The process according to any one of claims 159 to 170, wherein the condensing-step solvent is an aprotic solvent selected from: benzene, cyclohexane, pentane, hexane, acetonitrile, toluene, cycloheptane, o-xylene, m-xylene, p-xylene, a mixture of xylenes, heptanes, n-heptane, octanes, n-octanes, ethylbenzene, and mixtures thereof.
 173. The process according to any one of claims 159 to 170, wherein the condensing-step solvent is acetonitrile or toluene.
 174. The process according to any one of claims 159 to 170, wherein the condensing-step solvent is acetonitrile.
 175. The process according to any one of claims 159 to 170, wherein the condensing-step solvent is toluene.
 176. The process according to any one of claims 159 to 175, wherein condensing is conducted at the boiling point of the condensing-step solvent.
 177. The process according to any one of claims 159 to 176, wherein condensing further comprises the removal of water.
 178. The process according to any one of claims 159 to 176, wherein condensing further comprises the removal of water using a Dean-Stark process, a desiccant, or a combination thereof.
 179. The process according to any one of claims 159 to 176, wherein condensing further comprises the removal of water using a desiccant.
 180. The process according to any one of claims 159 to 176, wherein condensing further comprises the removal of water using a Dean-Stark process.
 181. The process according to any one of claims 159 to 180, wherein condensing further comprises the step of isolating the Compound of Formula (Ie) from a condensing-step mixture comprising the Compound of Formula (Ie) and the Compound of Formula (Ic).
 182. The process according to claim 181, wherein isolating comprises substantially removing the Compound of Formula (Ic) from the condensing-step mixture using an isolating-step acid.
 183. The process according to claim 182, wherein the isolating-step acid is a water-soluble acid.
 184. The process according to claim 182, wherein the isolating-step acid is an ammonium halide.
 185. The process according to claim 182, wherein the isolating-step acid is ammonium chloride.
 186. The process according to any one of claims 159 to 185, wherein R^(1c), R^(2c), and R^(3c) are each independently selected from: H, methoxy, methyl, trifluoromethyl, fluoro, chloro, and bromo.
 187. The process according to any one of claims 159 to 185, wherein R^(1c), R^(2c), and R^(3c) are each H.
 188. The process according to any one of claims 159 to 187, wherein condensing is conducted with stirring.
 189. A process for preparing 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A),

comprising: reacting 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A):

with an organomagnesium reagent of 4-bromo-2-fluoro-1-methylbenzene in the presence of a reacting-step solvent to form 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A).
 190. The process according to claim 189, wherein the organomagnesium reagent of 4-bromo-2-fluoro-1-methylbenzene is prepared by the process comprising the steps of: forming a first-reacting mixture comprising magnesium and the reacting-step solvent; adding a magnesium activator to the first-reacting mixture at a first-reacting temperature to form a second-reacting mixture; and adding 4-bromo-2-fluoro-1-methylbenzene to the second-reacting mixture at a second-reacting temperature to form the organomagnesium reagent of 4-bromo-2-fluoro-1-methylbenzene.
 191. The process according to claim 190, wherein the first-reacting temperature is about 15° C. to about 45° C.
 192. The process according to claim 190, wherein the first-reacting temperature is about 25° C. to about 40° C.
 193. The process according to claim 190, wherein the first-reacting temperature is about 25° C. to about 35° C.
 194. The process according to any one of claims 190 to 193, wherein the second-reacting temperature is about 20° C. to about 65° C.
 195. The process according to any one of claims 190 to 193, wherein the second-reacting temperature is about 25° C. to about 60° C.
 196. The process according to any one of claims 190 to 193, wherein the second-reacting temperature is about 30° C. to about 50° C.
 197. The process according to any one of claims 190 to 196, wherein the magnesium activator is I₂, 1,2-dibromoethane, diisobutylaluminium hydride (DIBAL-H), LiAlH₄, NaBH₄, sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al), and borane dimethyl sulfide complex (BH₃-SMe₂).
 198. The process according to any one of claims 190 to 196, wherein the magnesium activator is diisobutylaluminium hydride (DIBAL-H).
 199. The process according to any one of claims 189 to 198, wherein the reacting-step solvent is an ether solvent.
 200. The process according to any one of claims 189 to 198, wherein the reacting-step solvent is selected from: diethyl ether, 1,2-dimethoxyethane (DME), tetrahydrofuran (THF), cyclopentyl methyl ether (CPME), and 2-methyltetrahydrofuran (2-MeTHF).
 201. The process according to any one of claims 189 to 198, wherein the reacting-step solvent is selected from: tetrahydrofuran (THF), cyclopentyl methyl ether (CPME), and 2-methyltetrahydrofuran (2-MeTHF).
 202. The process according to any one of claims 189 to 198, wherein the reacting-step solvent is tetrahydrofuran (THF).
 203. The process according to any one of claims 189 to 202, wherein the organomagnesium reagent of 4-bromo-2-fluoro-1-methylbenzene is:

.
 204. The process according to any one of claims 189 to 203, wherein reacting is conducted with stirring.
 205. A process for preparing 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A),

comprising: coupling 2-cyclopropylacetic acid (Compound 1A) with N,O-dimethylhydroxylamine or a salt thereof in the presence of a coupling-step reagent, a coupling-step base, and a coupling-step solvent to form 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A).
 206. The process according to claim 205, further comprising mixing 2-cyclopropylacetic acid (Compound 1A), the coupling-step reagent, and the coupling-step solvent together to form a first-coupling mixture.
 207. The process according to claim 206, wherein the first-coupling mixture is at a first-coupling temperature of about -15° C. to about 35° C.
 208. The process according to claim 206, wherein the first-coupling mixture is at a first-coupling temperature of about -10° C. to about 30° C.
 209. The process according to claim 206, wherein the first-coupling mixture is at a first-coupling temperature of about -10° C. to about 25° C.
 210. The process according to claim 206, wherein the first-coupling mixture is at a first-coupling temperature of ≤ 25° C.
 211. The process according to any one of claims 205 to 210, wherein coupling further comprising adding N,O-dimethylhydroxylamine or a salt thereof to the first-coupling mixture to form a second-coupling mixture at a second-coupling temperature.
 212. The process according to claim 211, wherein the second-coupling temperature is ≤ 30° C.
 213. The process according to claim 211, wherein the second-coupling temperature is about -15° C. to about 30° C.
 214. The process according to claim 211, wherein the second-coupling temperature is about -10° C. to about 25° C.
 215. The process according to claim 211, wherein the second-coupling temperature is about 20° C. to about 25° C.
 216. The process according to any one of claims 211 to 215, wherein N,O-dimethylhydroxylamine or a salt thereof is added to the first-coupling mixture at a rate to maintain the temperature at the second-coupling temperature.
 217. The process according to any one of claims 211 to 216, further comprising adding the coupling-step base to the second-coupling mixture.
 218. The process according to any one of claims 211 to 216, further comprising adding the coupling-step base to the second-coupling mixture and maintaining a third-coupling temperature at about -10° C. to about 25° C.
 219. The process according to any one of claims 211 to 216, further comprising adding the coupling-step base to the second-coupling mixture and maintaining a third-coupling temperature at about 20° C. to about 25° C.
 220. The process according to any one of claims 205 to 219, wherein the coupling-step reagent is a tetramethyluronium-based coupling reagent.
 221. The process according to any one of claims 205 to 219, wherein the coupling-step reagent is a tetramethyluronium-based coupling agent selected from: 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 2-(6-chloro-1H benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate (HCTU), and N,N,N′,N′-tetramethyl-O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)uranium tetrafluoroborate (TDBTU).
 222. The process according to any one of claims 205 to 219, wherein the coupling-step reagent is 1,1′-carbonyldiimidazole (CDI).
 223. The process according to any one of claims 205 to 222, wherein the coupling-step solvent is an aprotic solvent.
 224. The process according to any one of claims 205 to 222, wherein the coupling-step solvent is selected from a halogenated solvent, an ether solvent, and mixtures thereof.
 225. The process according to any one of claims 205 to 222, wherein the coupling-step solvent comprises dichloromethane (DCM).
 226. The process according to any one of claims 205 to 225, wherein the coupling-step base is a tertiary amine.
 227. The process according to any one of claims 205 to 225, wherein the coupling-step base is selected from: N,N-diisopropylethylamine (DIEA), triethylamine (TEA), N-methylmorpholine (NMM), 4-dimethylaminopyridine (DMAP), 2,4,6-trimethylpyridine (collidine), 2,3,5,6-tetramethylpyridine (TEMP), and 2,6-di-tert-butyl-4-(dimethylamino)pyridine (DBDMAP).
 228. The process according to any one of claims 205 to 225, wherein the coupling-step base is triethylamine.
 229. The process according to any one of claims 205 to 228, wherein coupling is conducted with stirring.
 230. An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base).
 231. An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(16)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least three peaks, in terms of 2θ, selected from the group consisting of: 6.0° ± 0.2°, 11.9° ± 0.2°, 13.9° ± 0.2°, 14.3° ± 0.2°, 16.8° ± 0.2°, 17.9° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8°± 0.2°, 22.3°± 0.2°, 23.2°± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 28.7°± 0.2°, 29.6°± 0.2°, 36.1°± 0.2°, and 43.5° ± 0.2°.
 232. An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 25.7° ± 0.2°.
 233. An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 14.3° ± 0.2°.
 234. The anhydrous crystalline form (Compound 1, free base) according to claim 233, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.3° ± 0.2°, and 25.7° ± 0.2°.
 235. The anhydrous crystalline form (Compound 1, free base) according to claim 233, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.3° ± 0.2°, and 19.7° ± 0.2°.
 236. An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 19.7° ± 0.2°.
 237. The anhydrous crystalline form (Compound 1, free base) according to claim 236, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 19.7° ± 0.2°, and 25.7° ± 0.2°.
 238. An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, and 25.7° ± 0.2°.
 239. The anhydrous crystalline form (Compound 1, free base) according to claim 238, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, and 25.7° ± 0.2°.
 240. The anhydrous crystalline form (Compound 1, free base) according to claim 238, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, and 29.6° ± 0.2°.
 241. The anhydrous crystalline form (Compound 1, free base) according to claim 238, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 22.3° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, and 29.6° ± 0.2°.
 242. The anhydrous crystalline form (Compound 1, free base) according to claim 238, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 22.3° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 29.6° ± 0.2°, and 43.5° ± 0.2°.
 243. The anhydrous crystalline form (Compound 1, free base) according to claim 238, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 22.3° ± 0.2°, 25.7° ± 0.2°, 24.2° ± 0.2°, 26.8° ± 0.2°, 29.6° ± 0.2°, and 43.5° ± 0.2°.
 244. The anhydrous crystalline form (Compound 1, free base) according to claim 238, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 22.3° ± 0.2°, 25.7° ± 0.2°, 24.2° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, and 43.5° ± 0.2°.
 245. The anhydrous crystalline form (Compound 1, free base) according to claim 238, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 25.7° ± 0.2°, 24.2° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, and 43.5° ± 0.2°.
 246. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 223, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern substantially as shown in Figure
 1. 247. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 246, wherein the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 81° C. to about 89.5° C.
 248. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 246, wherein the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 82° C. to about 88° C.
 249. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 246, wherein the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 82.5° C. to about 88.5° C.
 250. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 246, wherein the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 83° C. to about 88° C.
 251. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 246, wherein the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 83.5° C. to about 87.5° C.
 252. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 246, wherein the anhydrous crystalline form has a differential scanning calorimetry thermogram substantially as shown in Figure
 2. 253. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 252, wherein the anhydrous crystalline form has a thermogravimetric analysis profile showing about 1.0% or less weight loss out to about 125° C.
 254. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 252, wherein the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.9% or less weight loss out to about 125° C.
 255. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 252, wherein the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.7% or less weight loss out to about 125° C.
 256. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 252, wherein the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.6% or less weight loss out to about 125° C.
 257. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 252, wherein the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.5% or less weight loss out to about 125° C.
 258. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 252, wherein the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.05% to about 1.0% weight loss out to about 125° C.
 259. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 252, wherein the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.1% to about 0.9% weight loss out to about 125° C.
 260. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 252, wherein the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.1% to about 0.7% weight loss out to about 125° C.
 261. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 252, wherein the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.1% to about 0.6% weight loss out to about 125° C.
 262. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 252, wherein the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.1% to about 0.4% weight loss out to about 125° C.
 263. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 252, wherein the anhydrous crystalline form has a thermogravimetric analysis profile substantially as shown in Figure
 2. 264. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.015% or less weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH.
 265. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.01% or less weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH.
 266. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.008% or less weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH.
 267. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.005% or less weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH.
 268. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.003% or less weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH.
 269. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing substantially no weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH.
 270. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.1% or less weight change from about 10% relative humidity (RH) to about 90% RH; and about 0.015% or less weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH.
 271. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.08% or less weight change from about 10% relative humidity (RH) to about 90% RH; and about 0.01% or less weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH.
 272. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.05% or less weight change from about 10% relative humidity (RH) to about 90% RH; and about 0.008% or less weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH.
 273. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.04% or less weight change from about 10% relative humidity (RH) to about 90% RH; and about 0.005% or less weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH.
 274. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.03% or less weight change from about 10% relative humidity (RH) to about 90% RH; and about 0.003% or less weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH.
 275. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.2% or less weight change from about 10% relative humidity (RH) to about 90% RH; and substantially no weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH.
 276. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile substantially as shown in Figure
 3. 277. An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has: an X-ray powder diffraction pattern comprising at least three peaks, in terms of 2θ, selected from the group consisting of: 6.0° ± 0.2°, 11.9° ± 0.2°, 13.9° ± 0.2°, 14.3° ± 0.2°, 16.8° ± 0.2°, 17.9° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, 36.1° ± 0.2°, and 43.5° ± 0.2°; a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 81° C. to about 89.5° C.; a thermogravimetric analysis profile showing about 0.05% to about 1.0% weight loss out to about 125° C.; and/or a gravimetric vapor sorption profile showing about 0.015% or less weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH.
 278. An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(l1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has: an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, and 25.7° ± 0.2°; a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 82.5° C. to about 88.5° C.; a thermogravimetric analysis profile showing about 0.7% or less weight loss out to about 125° C.; and/or a gravimetric vapor sorption profile showing about 0.005% or less weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH.
 279. An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has: an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 22.3° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 29.6° ± 0.2°, and 43.5° ± 0.2°; a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 83° C. to about 88° C.; a thermogravimetric analysis profile showing about 0.5% or less weight loss out to about 125° C.; and/or a gravimetric vapor sorption profile showing about 0.003% or less weight change after an adsorption/desorption cycle from 10% RH to 90% RH and back to 10% RH.
 280. An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has: an X-ray powder diffraction pattern substantially as shown in Figure 1; a differential scanning calorimetry thermogram substantially as shown in Figure 2; a thermogravimetric analysis profile substantially as shown in Figure 2; and/or a gravimetric vapor sorption profile substantially as shown in Figure
 3. 281. An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline is prepared by the process according to claim
 81. 282. A crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt).
 283. A crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt), wherein the crystalline form has an X-ray powder diffraction pattern comprising at least three peaks, in terms of 2θ, selected from the group consisting of: 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 16.3° ± 0.2°, 19.0° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 22.8° ± 0.2°, 23.3° ± 0.2°, 23.8° ± 0.2°, and 28.5° ± 0.2°.
 284. A crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt), wherein the crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 9.1° ± 0.2°.
 285. A crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt), wherein the crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 21.1° ± 0.2°.
 286. A crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt), wherein the crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ, at 23.3° ± 0.2°.
 287. A crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt), wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 21.1° ± 0.2°, and 23.3° ± 0.2°.
 288. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 11.3° ± 0.2°, 21.1° ± 0.2°, and 23.3° ± 0.2°.
 289. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 11.3° ± 0.2°, 21.1° ± 0.2°, 22.8° ± 0.2°, and 23.3° ± 0.2°.
 290. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 16.3° ± 0.2°, and 21.1° ± 0.2°.
 291. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 11.3° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° ± 0.2°.
 292. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 11.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° ± 0.2°.
 293. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° ± 0.2°.
 294. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 19.0° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° ± 0.2°.
 295. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° ± 0.2°.
 296. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, 23.8° ± 0.2°, and 28.5° ± 0.2°.
 297. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 19.0° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° ± 0.2°.
 298. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° ± 0.2°.
 299. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, 23.8° ± 0.2°, and 28.5° ± 0.2°.
 300. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 16.3° ± 0.2°, 19.0° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° ± 0.2°.
 301. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 16.3° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° ± 0.2°.
 302. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 16.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, 23.8° ± 0.2°, and 28.5° ± 0.2°.
 303. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 19.0° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, 23.8° ± 0.2°, and 28.5° ± 0.2°.
 304. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 16.3° ± 0.2°, 19.0° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, 23.8° ± 0.2°, and 28.5° ± 0.2°.
 305. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 304, wherein the crystalline form has an X-ray powder diffraction pattern substantially as shown in Figure
 24. 306. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 305, wherein the crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 154° C. to about 159° C.
 307. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 305, wherein the crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 154.5° C. to about 158.5° C.
 308. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 305, wherein the crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 155° C. to about 158° C.
 309. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 305, wherein the crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 155° C. to about 158° C.
 310. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 305, wherein the crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 155.5° C. to about 157.5° C.
 311. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 305, wherein the crystalline form has a differential scanning calorimetry thermogram substantially as shown in Figure
 25. 312. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 311, wherein the crystalline form has a thermogravimetric analysis profile showing about 1.0% or less weight loss out to about 125° C.
 313. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 311, wherein the crystalline form has a thermogravimetric analysis profile showing about 0.9% or less weight loss out to about 125° C.
 314. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 311, wherein the crystalline form has a thermogravimetric analysis profile showing about 0.7% or less weight loss out to about 125° C.
 315. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 311, wherein the crystalline form has a thermogravimetric analysis profile showing about 0.6% or less weight loss out to about 125° C.
 316. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 311, wherein the crystalline form has a thermogravimetric analysis profile showing about 0.5% or less weight loss out to about 125° C.
 317. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 311, wherein the crystalline form has a thermogravimetric analysis profile showing about 0.05% to about 1.0% weight loss out to about 125° C.
 318. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 311, wherein the crystalline form has a thermogravimetric analysis profile showing about 0.1% to about 0.9% weight loss out to about 125° C.
 319. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 311, wherein the crystalline form has a thermogravimetric analysis profile showing about 0.2% to about 0.7% weight loss out to about 125° C.
 320. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 311, wherein the crystalline form has a thermogravimetric analysis profile showing about 0.3% to about 0.6% weight loss out to about 125° C.
 321. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 311, wherein the crystalline form has a thermogravimetric analysis profile showing about 0.4% to about 0.5% weight loss out to about 125° C.
 322. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 311, wherein the crystalline form has a thermogravimetric analysis profile substantially as shown in Figure
 25. 323. A crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt), wherein the crystalline form has: an X-ray powder diffraction pattern comprising at least three peaks, in terms of 2θ, selected from the group consisting of: 9.1°±0.2°, 10.5° ±0.2°, 11.3°±0.2°, 13.2°±0.2°, 16.3°±0.2°, 19.0° ±0.2°, 19.3° ±0.2°, 20.4°±0.2°, 21.1°±0.2°, 22.8° ±0.2°, 23.3° ±0.2°, 23.8°±0.2°, and 28.5° ±0.2°; a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 154° C. to about 159° C.; and/or a thermogravimetric analysis profile showing about 0.05% to about 1.0% weight loss out to about 125° C.
 324. A crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt), wherein the crystalline form has: an X-ray powder diffraction pattern comprising peaks, in terms of 2θ,at 9.1°±0.2°, 11.3°±0.2°, 21.1°±0.2°, 22.8° ±0.2°, and 23.3°±0.2°; a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 155° C. to about 158° C.; and/or a thermogravimetric analysis profile showing about 0.9% or less weight loss out to about 125° C.
 325. A crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt), wherein the crystalline form has: an X-ray powder diffraction pattern comprising peaks, in terms of 2θ,at 9.1°±0.2°, 11.3°±0.2°, 13.2° ±0.2°, 16.3°±0.2°, and 21.1°±0.2°; a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 155.5° C. to about 157.5° C.; and/or a thermogravimetric analysis profile showing about 0.6% or less weight loss out to about 125° C.
 326. A crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt), wherein the crystalline form has: an X-ray powder diffraction pattern substantially as shown in Figure 24; a differential scanning calorimetry thermogram substantially as shown in Figure 25; and/or a thermogravimetric analysis profile substantially as shown in Figure
 25. 327. A pharmaceutical composition comprising a crystalline form (Compound 1, free base) according to any one of claims 230 to 281, and a pharmaceutically acceptable carrier.
 328. The pharmaceutical composition according to claim 327, wherein the composition is adapted for oral administration.
 329. The pharmaceutical composition according to claim 327 or 328, wherein the composition is in the form of a tablet or capsule.
 330. A pharmaceutical product selected from: a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a crystalline form (Compound 1, free base) according to any one of claims 230 to
 281. 331. A pharmaceutical composition comprising a crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 326, and a pharmaceutically acceptable carrier.
 332. The pharmaceutical composition according to claim 331, wherein the composition is adapted for oral administration.
 333. The pharmaceutical composition according to claim 331 or 332, wherein the composition is in the form of a tablet or capsule.
 334. A pharmaceutical product selected from: a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to
 326. 335. A composition comprising: a. 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), or a pharmaceutically acceptable salt thereof; and b. at least one compound selected from: (S)-4-(2-Chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A); (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(p-tolyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine(Compound IIa); (S)-4-(2-chloro-5-methyl-4-(prop-2-yn-1-yloxy)phenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N (prop-2-yn-1-yl)thiazol-2-amine (Compound IIb); 4-(2-chloro-4-methoxy-5-methylphenyl)-N [(1R)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-(2-propyn-1-yl)-2-thiazolamine (Compound IIc); ethanol; and propargyl bromide.
 336. The composition according to claim 335, wherein 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) is the free base.
 337. The composition according to claim 335 or 336, wherein the composition contains at least 97% of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) as determined by HPLC.
 338. The composition according to claim 335 or 336, wherein the composition contains at least 98% of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) as determined by HPLC.
 339. The composition according to claim 335 or 336, wherein the composition contains at least 99% of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) as determined by HPLC.
 340. The composition according to any one of claims 335 to 339, wherein the composition contains no more than 0.3% of (S)-4-(2-Chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) as determined by HPLC.
 341. The composition according to any one of claims 335 to 339, wherein the composition contains no more than 0.2% of (S)-4-(2-Chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) as determined by HPLC.
 342. The composition according to any one of claims 335 to 339, wherein the composition contains no more than 0.1%of (S)-4-(2-Chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) as determined by HPLC.
 343. The composition according to any one of claims 335 to 342, wherein the composition contains no more than 0.8% of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-l-(p-tolyl)ethyl)-5-methyl-N (prop-2-yn-1-yl)thiazol-2-amine (Compound IIa) as determined by HPLC.
 344. The composition according to any one of claims 335 to 342, wherein the composition contains no more than 0.7% of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-l-(p-tolyl)ethyl)-5-methyl-N (prop-2-yn-1-yl)thiazol-2-amine (Compound IIa) as determined by HPLC.
 345. The composition according to any one of claims 335 to 342, wherein the composition contains no more than 0.6% of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-l-(p-tolyl)ethyl)-5-methyl-N (prop-2-yn-1-yl)thiazol-2-amine (Compound IIa) as determined by HPLC.
 346. The composition according to any one of claims 335 to 345, wherein the composition contains no more than 0.15% of (S)-4-(2-chloro-5-methyl-4-(prop-2-yn-1-yloxy)phenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N (prop-2-yn-1-yl)thiazol-2-amine (Compound IIb)as determined by HPLC.
 347. The composition according to any one of claims 335 to 345, wherein the composition contains no more than 0.1%of (S)-4-(2-chloro-5-methyl-4-(prop-2-yn-1-yloxy)phenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIb)as determined by HPLC.
 348. The composition according to any one of claims 335 to 345, wherein the composition contains no more than 0.05% of (S)-4-(2-chloro-5-methyl-4-(prop-2-yn-1-yloxy)phenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N (prop-2-yn-1-yl)thiazol-2-amine (Compound IIb)as determined by HPLC.
 349. The composition according to any one of claims 335 to 348, wherein the composition contains no more than 0.3% of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1R)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-(2-propyn-1-yl)-2-thiazolamine (Compound IIc)as determined by chiral HPLC.
 350. The composition according to any one of claims 335 to 348, wherein the composition contains no more than 0.2% of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1R)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-(2-propyn-1-yl)-2-thiazolamine (Compound IIc)as determined by chiral HPLC.
 351. The composition according to any one of claims 335 to 348, wherein the composition contains no more than 0.1% of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1R)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-(2-propyn-1-yl)-2-thiazolamine (Compound IIc)as determined by chiral HPLC.
 352. The composition according to any one of claims 335 to 351, wherein the composition contains no more than 5000 ppm of ethanol as determined by gas chromatography.
 353. The composition according to any one of claims 335 to 351, wherein the composition contains no more than 3000 ppm of ethanol as determined by gas chromatography.
 354. The composition according to any one of claims 335 to 351, wherein the composition contains no more than 1000 ppm of ethanol as determined by gas chromatography.
 355. The composition according to any one of claims 335 to 354, wherein the composition contains no more than 200 ppm of propargyl bromide as determined by gas chromatography.
 356. The composition according to any one of claims 335 to 354, wherein the composition contains no more than 100 ppm of propargyl bromide as determined by gas chromatography.
 357. The composition according to any one of claims 335 to 354, wherein the composition contains no more than 30 ppm of propargyl bromide as determined by gas chromatography.
 358. The composition according to any one of claims 335 to 357, wherein 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base) is anhydrous crystalline Form I.
 359. The composition according to any one of claims 335 to 359, further comprising a pharmaceutically acceptable excipient.
 360. A method of treating a disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form (Compound 1, free base) according to any one of claims 230 to 281; a crystalline form (Compound 1, tosylate base) according to any one of claims 282 to 326; a pharmaceutical composition according to any one of claims 327 to 329 and 331 to 333; a pharmaceutical product according to claim 330 or 334; or a composition according to any one of claims 335 to 359; wherein the subject has abnormal levels of CRF₁.
 361. A method of treating a Corticotropin Releasing Factor 1(CRF₁)disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form (Compound 1, free base) according to any one of claims 230 to 281; a crystalline form (Compound 1, tosylate base) according to any one of claims 282 to 326; a pharmaceutical composition according to any one of claims 327 to 329 and 331 to 333; a pharmaceutical product according to claim 330 or 334; or a composition according to any one of claims 335 to
 359. 362. A method of treating congenital adrenal hyperplasia (CAH), in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form (Compound 1, free base) according to any one of claims 230 to 281; a crystalline form (Compound 1, tosylate base) according to any one of claims 282 to 326; a pharmaceutical composition of any one of claims 327 to 329 and 331 to 333; a pharmaceutical product according to claim 330 or 334; or a composition according to any one of claims 335 to
 359. 363. The use of an anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 281; or the crystalline form (Compound 1, tosylate base) according to any one of claims 282 to 326; for the manufacture of a medicament for the treatment of a subject wherein the subject has abnormal levels of CRF₁.
 364. The use of an anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 281; or the crystalline form (Compound 1, tosylate base) according to any one of claims 282 to 326; for the manufacture of a medicament for the treatment of a Corticotropin Releasing Factor 1(CRF₁)disorder.
 365. The use of an anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 281; or the crystalline form (Compound 1, tosylate base) according to any one of claims 282 to 326; for the manufacture of a medicament for the treatment of congenital adrenal hyperplasia (CAH).
 366. An anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 281; a crystalline form (Compound 1, tosylate base) according to any one of claims 282 to 326; a pharmaceutical composition according to any one of claims 327 to 329 and 331 to 333; a pharmaceutical product according to claim 330 or 334; or a composition according to any one of claims 335 to 359; for use in a method of treatment of the human or animal body by therapy.
 367. An anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 281; a crystalline form (Compound 1, tosylate base) according to any one of claims 282 to 326; a pharmaceutical composition according to any one of claims 327 to 329 and 331 to 333; a pharmaceutical product according to claim 330 or 334; or a composition according to any one of claims 335 to 359; for use in a method of treatment of a disorder in a subject wherein the subject has abnormal levels of CRF₁.
 368. An anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 281; a crystalline form (Compound 1, tosylate base) according to any one of claims 282 to 326; a pharmaceutical composition according to any one of claims 327 to 329 and 331 to 333; a pharmaceutical product according to claim 330 or 334; or a composition according to any one of claims 335 to 359; for use in a method of treatment of a Corticotropin Releasing Factor 1(CRF₁)disorder.
 369. An anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 281; a crystalline form (Compound 1, tosylate base) according to any one of claims 282 to 326; a pharmaceutical composition according to any one of claims 327 to 329 and 331 to 333; a pharmaceutical product according to claim 330 or 334; or a composition according to any one of claims 335 to 359; for use in a method of treating congenital adrenal hyperplasia (CAH).
 370. A Compound of Formula (Ie):

wherein: R^(1c),R^(2c),and R^(3c)are each independently selected from: H, C₁-C₆alkoxy, C₁-C₆alkyl, C₁-C₆haloalkyl, and halogen.
 371. The compound according to claim 370, wherein R^(1c),R^(2c),and R^(3c) are each independently selected from: H, methoxy, methyl, trifluoromethyl, fluoro, chloro, and bromo.
 372. The compound according to claim 370, wherein R^(1c),R^(2c),and R^(3c) are each H.
 373. A Compound of Formula (Ig) or a salt thereof:

wherein: R^(1c),R^(2c),and R^(3c)are each independently selected from: H, C₁-C₆alkoxy, C₁-C₆alkyl, C₁-C₆haloalkyl, and halogen.
 374. The compound according to claim 373, wherein R^(1c),R^(2c),and R^(3c)are each independently selected from: H, methoxy, methyl, trifluoromethyl, fluoro, chloro, and bromo.
 375. The compound according to claim 373, wherein R^(1c),R^(2c),and R^(3c)are each H.
 376. The compound according to any one of claims 373 to 375, wherein the compound is an HC1 salt.
 377. The compound according to claim 376, wherein the HC1salt is crystalline.
 378. A process for preparing a pharmaceutical composition comprising admixing a crystalline form (Compound 1, free base) according to any one of claims 230 to 281; a crystalline form (Compound 1, tosylate base) according to any one of claims 282 to 326; or a composition according to any one of claims 335 to 359; and a pharmaceutically acceptable carrier. 